Heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders

ABSTRACT

Compounds and methods are provided for the treatment of, inter alia, Type II diabetes and other diseases associated with poor glycemic control. The compounds of the invention are orally active.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/612,451 filed on Sep. 12, 2012, which is a continuation of U.S.patent application Ser. No. 12/619,577 filed on Nov. 16, 2009, now U.S.Pat. No. 8,288,384, which is a divisional of U.S. patent applicationSer. No. 11/964,461, filed on Dec. 26, 2007, now U.S. Pat. No.7,638,541, which claims the benefit under 35 U.S.C. 119(e) to U.S.Provisional Application No. 60/877,903 filed on Dec. 28, 2006, thedisclosures of each of which are incorporated herein by reference intheir entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

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BACKGROUND OF THE INVENTION

Diabetes mellitus can be divided into two clinical syndromes, Type I andType II diabetes mellitus. Type I diabetes, or insulin-dependentdiabetes mellitus, is a chronic autoimmune disease characterized by theextensive loss of beta cells in the pancreatic islets of Langerhans(hereinafter referred to as “pancreatic islet cells” or “islet cells”),which produce insulin. As these cells are progressively destroyed, theamount of secreted insulin decreases, eventually leading tohyperglycemia (abnormally high level of glucose in the blood) when theamount secreted drops below the level required for euglycemia (normalblood glucose level). Although the exact trigger for this immuneresponse is not known, patients with Type I diabetes have high levels ofantibodies against pancreatic beta cells (hereinafter “beta cells”).However, not all patients with high levels of these antibodies developType I diabetes.

Type II diabetes, or non-insulin-dependent diabetes mellitus, developswhen muscle, fat and liver cells fail to respond normally to insulin.This failure to respond (called insulin resistance) may be due toreduced numbers of insulin receptors on these cells, or a dysfunction ofsignaling pathways within the cells, or both. The beta cells initiallycompensate for this insulin resistance by increasing their insulinoutput. Over time, these cells become unable to produce enough insulinto maintain normal glucose levels, indicating progression to Type IIdiabetes (Kahn S E, Am. J. Med. (2000) 108 Suppl 6a, 2S-8S).

The fasting hyperglycemia that characterizes Type II diabetes occurs asa consequence of the combined lesions of insulin resistance and betacell dysfunction. The beta cell defect has two components: the firstcomponent, an elevation of basal insulin release (occurring in thepresence of low, non-stimulatory glucose concentrations), is observed inobese, insulin-resistant pre-diabetic stages as well as in Type IIdiabetes. The second component is a failure to increase insulin releaseabove the already elevated basal output in response to a hyperglycemicchallenge. This lesion is absent in pre-diabetes and appears to definethe transition from normo-glycemic insulin-resistant states to frankdiabetes. There is currently no cure for diabetes. Conventionaltreatments for diabetes are very limited, and focus on attempting tocontrol blood glucose levels in order to minimize or delaycomplications. Current treatments target either insulin resistance(metformin, thiazolidinediones (“TZD5”)), or insulin release from thebeta cell (sulphonylureas, exanatide). Sulphonylureas, and othercompounds that act by depolarizing the beta cell, have the side effectof hypoglycemia since they cause insulin secretion independent ofcirculating glucose levels. One approved drug, Byetta (exanatide)stimulates insulin secretion only in the presence of high glucose, butis not orally available and must be injected. Januvia (sitagliptin) isanother recently approved drug that increases blood levels of incretinhormones, which can increase insulin secretion, reduce glucagonsecretion and have other less well characterized effects. However,Januvia and other dipeptidyl peptidases IV inhibitors may also influencethe tissue levels of other hormones and peptides, and the long-termconsequences of this broader effect have not been fully investigated.There is an unmet need for oral drugs that stimulate insulin secretionin a glucose dependent manner.

Progressive insulin resistance and loss of insulin secreting pancreaticβ-cells are primary characteristics of Type II diabetes. Normally, adecline in the insulin sensitivity of muscle and fat is compensated forby increases in insulin secretion from the β-cell. However, loss ofβ-cell function and mass results in insulin insufficiency and diabetes(Kahn B B, Cell 92:593-596, 1998; Cavaghan M K, et al., J. Clin. Invest.106:329-333. 2000; Saltiel A R, Cell 104:517-529, 2001; Prentki M andNolan C J. J Clin Invest. 116:1802-1812. (2006); and Kahn S E. J. Clin.Endocrinol. Metab. 86:4047-4058, 2001). Hyperglycemia furtheraccelerates the decline in β-cell function (UKPDS Group, J.A.M.A.281:2005-2012, 1999; Levy J, et al., Diabetes Med. 15:290-296, 1998; andZhou Y P, et al., J Biol Chem 278:51316-23, 2003). Several of the genesin which allelic variation is associated with an increased risk of TypeII diabetes are expressed selectively in the beta cell (Bell G I andPolonsky K S, Nature 414:788-791 (2001); Saxena R, et al., Science.(2007) Apr. 26; [Epub ahead of print]; and Valgerdur Steinthorsdottir,et al., Nature Genetics (2007) Apr. 26; [Epub ahead of print]).

Insulin secretion from the beta cells of pancreatic islets is elicitedby increased levels of blood glucose. Glucose is taken up into the betacell primarily by the beta cell and liver selective transporter GLUT2(Thorens B. Mol Membr Biol. 2001 October-December; 18(4):265-73). Onceinside the cell, glucose is phosphorylated by glucokinase, which is theprimary glucose sensor in the beta cell since it catalyzes theirreversible rate limiting step for glucose metabolism (Matschinsky F M.Curr Diab Rep. 2005 June; 5(3):171-6). The rate of glucose-6-phosphateproduction by glucokinase is dependent on the concentration of glucosearound the beta cell, and therefore this enzyme allows for a directrelationship between level of glucose in the blood and the overall rateof glucose oxidation by the cell. Mutations in glucokinase produceabnormalities in glucose dependent insulin secretion in humans givingfurther evidence that this hexokinase family member plays a key role inthe islet response to glucose (Gloyn A L, et al., J Biol. Chem. 2005Apr. 8; 280(14):14105-13. Epub 2005 Jan. 25). Small molecule activatorsof glucokinase enhance insulin secretion and may provide a route fortherapeutic exploitation of the role of this enzyme (Guertin K R andGrimsby J. Curr Med. Chem. 2006; 13(15):1839-43; and Matschinsky F M, etal., Diabetes 2006 January; 55(1):1-12) in diabetes. Glucose metabolismvia glycolysis and mitochondrial oxidative phosphorylation ultimatelyresults in ATP production, and the amount of ATP produced in a beta cellis directly related to the concentration of glucose to which the betacell is exposed.

Elevated ratios of ATP to ADP that occur in the presence of higherglucose result in the closure of the Kir6.2 channel via interaction withthe SUR1 subunit of the channel complex. Closure of these channels onthe plasma membrane of the beta cell results in de-polarization of themembrane and subsequent activation of voltage dependent calcium channels(VDCCs) (Ashcroft F M, and Gribble F M, Diabetologia 42:903-919, 1999;and Seino S, Annu Rev Physiol. 61:337-362, 1999). Calcium ion entry aswell as release of calcium from intracellular stores triggers exocytosisof insulin granules, resulting is secretion of insulin into the bloodstream. Agents which close the Kir6.2 channel such as sulphonylureas andmetaglitinides (Rendell M. Drugs 2004; 64(12):1339-58; and Blickle J F,Diabetes Metab. 2006 April; 32(2):113-20) also cause membranedepolarization, and therefore these agents stimulate insulin secretionin a glucose independent fashion. Potassium channel openers, such asdiazoxide, inhibit insulin secretion by preventing elevated ATP/ADPratios from closing the Kir6.2 channel (Hansen J B. Curr Med. Chem.2006; 13(4):361-76). Calcium channel blockers, such as verapamil andnifedipine, can also inhibit insulin secretion (Henquin, J. C. (2004)Diabetes 53, S48-S58). Although sulfonylureas and metaglitinides areeffective glucose lowering agents in the clinic, they act independentlyof blood glucose levels. Because they act independently of glucoselevels, these drugs may result in hypoglycemia.

Glucose dependent insulin secretion from the beta cell is dependent onnumerous neurotransmitters and blood-borne hormones, as well as local,intra-islet factors. CNS activation of the vagal innervation of theislet can lead to the release of small molecules such as acetylcholineand peptides such as vasoactive intestinal polypeptide (VIP), gastrinreleasing peptide (GRP) and Pituitary Adenylate Cyclase ActivatingPeptide (PACAP). Acetylcholine activation of phospholipase C through theG_(αq)-coupled GPCR M3 muscarinic receptor leads to release of Ca++ fromintracellular stores (Gilon P, and Henquin J C. Endocr Rev. 2001October; 22(5):565-604). Cholinergic agonists also lead to a subtleNa+-dependent plasma membrane depolarization that can work in concertwith glucose-initiated depolarization to enhance insulin release (GilonP, and Henquin J C. Endocr Rev. 2001 October; 22(5):565-604). VIP andPACAP each bind to an overlapping set of G_(α)-coupled GPCRs (PAC1,VIPR1, and VIPR2) on the beta cell that lead to stimulation of adenylatecyclase and an increase in intracellular cAMP (Filipsson K, et al.,Diabetes, 2001 September; 50(9):1959-69; Yamada H, et al., Regul Pept.2004 Dec. 15; 123(1-3):147-53; and Qader S S, et al., Am J PhysiolEndocrinol Metab. 2007 May; 292(5):E1447-55).

Elevation of beta cell cAMP has a substantial potentiating effect oninsulin secretion in the presence of stimulatory levels of glucose (seebelow). Unfortunately, many potentiators of glucose-stimulated insulinsecretion also have effects outside of the islet which limit theirability to be used as diabetes therapeutics. For example, the bestavailable selective muscarinic agonists which stimulate insulinsecretion also stimulate multiple undesirable responses in multipletissues (Rhoades R A and Tanner G A, eds. (2003) Medical Physiology, 2nded. Lippincott, Williams and Wilkins. ISBN 0-7817-1936-4). Likewise, VIPand PACAP receptors are present in multiple organ systems and mediateeffects on the reproductive, immune and other diverse systems that makethem less attractive as specific enhancers of glucose dependent insulinsecretion.

Incretin hormones such as Glucagon-Like Peptide 1 (GLP-1) andGlucose-dependent Insulinotropic Polypeptide (GIP, also known as GastricInhibitory Polypeptide) also bind to specific Galpha_(s)-coupled GPCRsreceptors on the surface of islet cells, including beta cells, and raiseintracellular cAMP (Drucker D J, J Clin Invest. 2007 January;117(1):24-32). Although the receptors for these hormones are present inother cells and tissues, the overall sum of effects of these peptidesappear to be beneficial to control of glucose metabolism in the organism(Hansotia T, et al., J Clin Invest. 2007 January; 117(1):143-52. Epub2006 Dec. 21). GIP and GLP-1 are produced and secreted from intestinal Kand L cells, respectively, and these peptide hormones are released inresponse to meals by both direct action of nutrients in the gut lumenand neural stimulation resulting from food ingestion. GIP and GLP-1 haveshort half-lives in human circulation due to the action of the proteasedipeptidyl-peptidase IV (DPP IV), and inhibitors of this protease canlower blood glucose due to their ability to raise the levels of activeforms of the incretin peptides. The glucose lowering that can beobtained with DPPIV inhibitors, however, is somewhat limited since thesedrugs are dependent on the endogenous release of the incretin hormones.Peptides (eg. exanatide (Byetta)) and peptide-conjugates that bind tothe GIP or GLP-1 receptors but are resistant to serum protease cleavagecan also lower blood glucose substantially (Gonzalez C, et al., ExpertOpin Investig Drugs 2006 August; 15(8):887-95), but these incretinmimetics must be injected and tend to induce a high rate of nausea andtherefore are not ideal therapies for general use in the Type IIdiabetic population. The clinical success of DPPIV inhibitors andincretin mimetics, though far from ideal, do point to the potentialutility of compounds that increase incretin activity in the blood ordirectly stimulate cAMP in the beta cell. Some studies have indicatedthat beta cell responsiveness to GIP is diminished in Type II diabetes(Nauck M A, et al., J. Clin. Invest. 91:301-307 (1993); and Elahi D, etal., Regul. Pept. 51:63-74 (1994)). Restoration of this responsiveness(Meneilly G S, et al., Diabetes Care. 1993 January; 16(1):110-4) may bea promising way to improve beta cell function in vivo.

Since increased incretin activity has a positive effect on glucosedependent insulin secretion and perhaps other mechanisms that lead tolower blood glucose, it is also of interest to explore therapeuticapproaches to increasing incretin release from intestinal K and L cells.GLP-1 secretion appears to be attenuated in Type II diabetes (VilsbollT, et al., Diabetes 50:609-613), so improving incretin release mayameliorate this component of metabolic dysregulation. Nutrients such asglucose and fat in the gut lumen prompt incretin secretion byinteraction with apical receptors (Vilsboll T, et al., Diabetes50:609-613). GLP-1 and GIP release can also result from neuralstimulation; acetylcholine and GRP can enhance incretin release in amanner perhaps analogous to the effects of these neurotransmitters onthe beta cell in regard to insulin secretion (Brubaker P, Ann NY Acad.Sci. 2006 July; 1070:10-26; and Reimann F, et al., Diabetes 2006December; 55 (Supplement 2):578-585). Somatostatin, leptin and freefatty acids also appear to modulate incretin secretion (Brubaker P, AnnNY Acad. Sci. 2006 July; 1070:10-26; and Reimann, F. et al., Diabetes.2006 December; 55(Supplement 2):578-S85). To date, however, there doesnot appear to be a way to selectively impact these pathways to promoteincretin secretion for therapeutic benefit. There is a need for oraldrugs that stimulate incretin secretion in the treatment of diabetes.

Incretins can also increase the rate of beta cell proliferation anddecrease the apoptotic rates of beta cells in animal models (Farilla L,et al., Endocrinology 2002 November; 143(11):4397-408) and human isletsin vitro (Farilla L, et al., Endocrinology 2003 December;144(12):5149-58). The net result of these changes is an increase in betacell number and islet mass, and this should provide for increasedinsulin secretory capacity, which is another desired aim ofanti-diabetic therapies. GLP-1 has also been shown to protect isletsfrom the destructive effects of agents such as streptozotocin byblocking apoptosis (Li Y, et al., J Biol. Chem. 2003 Jan. 3;278(1):471-8). Cyclin D1, a key regulator of progression through thecell cycle, is up-regulated by GLP-1, and other agents that increasecAMP and PKA activity also have a similar effect (Friedrichsen B N, etal., J Endocrinol. 2006 March; 188(3):481-92; and Kim M J, et al., JEndocrinol. 2006 March; 188(3):623-33). Increased transcription of thecyclin D1 gene occurs in response to PKA phosphorylation of CREB(cAMP-response element binding) transcription factors (Hussain M A, etal., Mol Cell Biol. 2006 October; 26(20):7747-59). There is a need fororal drugs that increase beta cell number and islet mass in thetreatment of diabetes.

Beta cell cAMP levels may also be raised by inhibiting the degradationof this second messenger by phosphodiesterases to AMP (Furman B, andPyne N, Curr Opin Investig Drugs 2006 October; 7(10):898-905). There areseveral different cAMP phosphodiesterases in the beta cell, and many ofthese have been shown to serve as a brake on glucose-dependent insulinsecretion Inhibitors of cAMP phosphodiesterases have been shown toincrease insulin secretion in vitro and in vivo, including PDE1C, PDE3B,PDE10, (Han P, et al., J Biol. Chem. 1999 Aug. 6; 274(32):22337-44;Harndahl L, et al., J Biol. Chem. 2002 Oct. 4; 277(40):37446-55; Walz HA, et al., J Endocrinol. 2006 June; 189(3):629-41; Choi Y H, et al., JClin Invest. 2006 December; 116(12):3240-51; and Cantin L D, et al.,Bioorg Med Chem. Lett. 2007 May 15; 17(10):2869-73) but so far, no PDEshave been found to have the cell type selectivity necessary to avoidundesirable effects. However, this remains an area of activeinvestigation due to the potential for amplification of the effects ofincretins and other agents that stimulate adenylate cyclase.

There appear to be multiple mechanisms by which cAMP elevation in thebeta cell can enhance glucose dependent insulin secretion. Classically,many of the intracellular effects of cAMP are mediated by thecAMP-dependent protein kinase (protein kinase A, PKA) (Hatakeyama H, etal., J Physiol. 2006 Jan. 15; 570(Pt 2):271-82). PKA consists of acomplex of two regulatory and two catalytic domains; binding of cAMP tothe catalytic domains releases the catalytic domains and results inincreased protein phosphorylation activity. One of the downstreameffects of this kinase activity is enhanced efficiency of insulinexocytosis (Gromada J, et al., Diabetes 1998 January; 47(1):57-65).Another cAMP binding protein is Epac, a guanine nucleotide exchangefactor (GEF) (Kashima Y, et al., J Biol. Chem. 2001 Dec. 7;276(49):46046-53. Epub 2001 Oct. 11; and Shibasaki T, et al., J Biol.Chem. 2004 Feb. 27; 279(9):7956-61), which mediates a cAMP-dependent,but PKA-independent, increase in insulin exocytosis. Epac activated bycAMP may also enhance of release of intracellular Ca++ (Holz G G,Diabetes 2004 January; 53(1):5-13). The effects of cAMP on insulinsecretion are dependent on elevated glucose levels, so raising cAMP inthe pancreatic beta cell is an important goal for therapeutics of TypeII diabetes.

Agents that raise intracellular cAMP levels in the beta cell increaseinsulin secretion in a glucose dependent manner (MiuraY and Matsui H,Am. J. Physiol Endocrinol. Metab (2003) 285, E1001-E1009). One mechanismfor raising cAMP is by the action of G-protein coupled cell surfacereceptors, which stimulate the enzyme adenylate cyclase to produce morecAMP. The GLP-1 receptor, which is the target of exanatide, is anexample of such a receptor (Thorens B, et al., Diabetes (1993) 42,1678-1682). There is a need for oral drugs that increase intracellularlevels of cAMP in the treatment of diabetes.

BRIEF SUMMARY OF THE INVENTION

Quite surprisingly, we now find that novel agonists of another G-proteincoupled receptor (“GPCR”), IC-GPCR2 is useful in the treatment ofdiabetes. IC-GPCR2 can also raise intracellular cAMP levels (see InVitro Activity Table 1 in Biological Example 1). IC-GPCR2 is alsoreferred to as RUP3 and GPR119. Such raised cAMP levels increase insulinsecretion in a glucose dependent manner (see Biological Examples 2, 3and 5) and thus provide a useful treatment for, inter alia, Type IIdiabetes. The novel agonists described in this invention are orallyactive (see Biological Examples 3 and 5), providing a significantdifferentiating feature to exanatide. Additionally, Biological Example 5provides data on the effect of GPR119 agonists on glucose levels,insulin secretion and weight in diabetic ZDF rats (see FIGS. 3, 4 and5). Biological Example 6 shows the triglyceride and glucose loweringeffects of the GPR119 agonists of the present invention. BiologicalExample 4 shows the tissue specific expression of GPR119. We have alsofound that nucleic acid probes corresponding to IC-GPCR2 are highlyenriched in pancreatic islets (the majority of which are beta cells),and are not detected in any other tissue examined (see FIGS. 1 and 2).This surprising occurrence means that the novel agonists described inthe current invention will be useful in diagnosing diseases effectingpancreatic islets (including beta cells) such as diabetes. Agonists ofIC-GPCR2 capable of raising intracellular cAMP levels have now beenidentified using a cell-based screen (see Biological Example 1).

The present invention provides compounds represented by Formula I:

as well as pharmaceutical compositions containing those compounds.

The present invention further provides compounds represented by FormulaII:

as well as pharmaceutical compositions containing compounds of FormulaII.

Also provided are methods of treating diseases such as Type II diabetesand other diseases and conditions using one or more of these compoundsor compositions, as described in further detail below. The inventionalso provides methods of raising intracellular levels of cyclic AMP(cAMP) by using one or more of the compounds described herein. Further,the compounds may be used to stimulate insulin production and stimulatesecretion of insulin, glucagon-like peptide 1 (GLP1), and glucosedependent insulinotropic polypeptide (GIP) in a mammal, in particular ahuman. Additionally, the compounds described herein are useful inlowering blood glucose when administered to a subject in need oftreatment to lower blood glucose. The compounds of the present inventionare also useful in lowering blood triglyceride levels in need of suchtreatment.

In a related aspect, the present invention provides methods ofdiagnosing a number of diseases and conditions using labeled compoundsof Formula I or Formula II.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates rat islet chip hybridization results demonstratingthe islet enrichment of IC-GPCR2 mRNA relative to other tissues. Chipswere hybridized with equivalent amounts of cRNA from five sets ofisolated rat islets, as well as the rat tissues: brain, duodenum,adipose (fat), kidney, liver, skeletal muscle, pancreas and spleen. The“Average Difference” score reflects the relative abundance of theIC-GPCR2 mRNA in each of the tissues. The Affymetrix GeneChip analysispackage called the IC-GPCR2 mRNA “Present” in four of five islet samplesand “Absent” in each of the other tissues.

FIG. 2 illustrates mouse islet chip hybridization results demonstratingthe islet enrichment of IC-GPCR2 mRNA relative to other tissues. Chipswere hybridized with equivalent amounts of cRNA from a pancreatic betacell line (betaHC9), four sets of isolated mouse islets, as well as themouse tissues: adipose (fat), brain, heart, kidney, liver, lung,pituitary, skeletal muscle, small intestine, thymus, hypothalamus,adrenal, thyroid and pancreas. The “Signal” score reflects the relativeabundance of the IC-GPCR2 mRNA in each of the tissues. The AffymetrixGeneChip analysis package called the IC-GPCR2 mRNA “Present” in betaHC9,and three of four islet samples. The Affymetrix GeneChip analysispackage called the IC-GPCR2 mRNA “Absent” in each of the other tissues.

FIG. 3 shows the changes in fed plasma glucose levels of female ZDF ratson a high fat diet. * p≦0.05 agonist 2 at 30 mg/kg and 100 mg/kg vs.high fat diet (HFD) vehicle. # p≦0.05 HFD vs. chow control, by 2 wayANOVA with Bonferroni post test. The experiment was performed asdescribed in Biological Example 5.

FIG. 4 shows the changes in fed plasma insulin levels of female ZDF ratson a high fat diet. * p≦0.05 agonist 2 at 30 mg/kg vs. high fat diet(HFD) vehicle, # p≦0.05 agonist 2 at 100 mg/kg vs. HFD vehicle, $ p≦0.05HFD vehicle vs Chow vehicle, by 2 way ANOVA with Bonferroni post test.The experiment was performed as described in Biological Example 5.

FIG. 5 shows the effect of 28 days of treatment with agonist 2 onfasting plasma glucose and insulin levels in female ZDF rats on high fatdiets. * p≦0.05 treatment vs. high fat diet (HFD) vehicle, # p≦0.05 HFDvehicle vs. Chow vehicle, by one way ANOVA with Dunnet's post test. Theexperiment was performed as described in Biological Example 5.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

The abbreviations used herein are conventional, unless otherwisedefined: AcOH: acetic acid; nBuLi: n-butyllithium; Cs₂CO₃: cesiumcarbonate; CH₂Cl₂: dichloromethane; CH₃MgI: methyl magnesium iodide;CuCl₂: copper chloride; DAST: (diethylamino)sulfur trifluoride; DEAD:diethyl azodicarboxylate; DIBAL: diisobutylaluminum hydride; DIPEA:diisopropylethylamine; DMSO: dimethyl sulfoxide; Et₃N: triethylamine;EtOAc: ethyl acetate; H₂: hydrogen; HBr: hydrogen bromide; HCl: hydrogenchloride; H₂O: water; H₂O₂: hydrogen peroxide; HPLC: high performanceliquid chromatography; KCN: potassium cyanide; LHMDS: lithiumhexamethyldisilazide; LiAlH₄: lithium aluminum hydride; LiOH: lithiumhydroxide; MeCN: acetonitrile; Met methyl iodide; MeOH: methanol; MgSO₄:magnesium sulfate; MgCO₃: magnesium carbonate; MsCl: mesyl chloride;NaHSO₃: sodium hydrogen sulfite; mCPBA: meta-chloroperoxybenzoic acid;N₂: nitrogen; Na₂CO₃: sodium carbonate; NaHCO₃: sodium bicarbonate;NaNO₂: sodium nitrite; NaOH: sodium hydroxide; Na₂S₂O₃: sodiumbisulfate; Na₂SO₄: sodium sulfate; NBS: N-bromosuccinimide; NH₄Cl:ammonium chloride; NH₄OAc: ammonium acetate; NMR: nuclear magneticresonance; Pd/C: palladium on carbon; PPh₃: triphenyl phosphine; iPrOH:isopropyl alcohol; SOCl₂: thionyl chloride; THF: tetrahydrofuran; TLC:thin layer chromatography.

Unless otherwise stated, the following terms used in the specificationand claims have the meanings given below:

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6carbon atoms. “C_(u-v)alkyl” refers to alkyl groups having from u to vcarbon atoms. This term includes, by way of example, linear and branchedhydrocarbyl groups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl(CH₃CH₂CH₂—), isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl((CH₃)₂CHCH₂—), sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—),n-pentyl (CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—).

“Substituted alkyl” refers to an alkyl group having from 1 to 5 and, insome embodiments, 1 to 3 or 1 to 2 substituents selected from the groupconsisting of alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido,carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy,cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino,substituted guanidino, halo, hydroxy, hydroxyamino, alkoxyamino,hydrazino, substituted hydrazino, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, spirocycloalkyl, SO₃H, substituted sulfonyl,sulfonyloxy, thioacyl, thiocyanate, thiol, alkylthio, and substitutedalkylthio, wherein said substituents are as defined herein.

“Alkylidene” or “alkylene” refers to divalent saturated aliphatichydrocarbyl groups having from 1 to 10 carbon atoms and, in someembodiments, from 1 to 6 carbon atoms. “(C_(u-v))alkylene” refers toalkylene groups having from u to v carbon atoms. The alkylidene andalkylene groups include branched and straight chain hydrocarbyl groups.For example “(C₁₋₆)alkylene” is meant to include methylene, ethylene,propylene, 2-methypropylene, pentylene, and the like.

“Substituted alkylidene” or “substituted alkylene” refers to analkylidene group having from 1 to 5 and, in some embodiments, 1 to 3 or1 to 2 substituents selected from the group consisting of alkoxy,substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido,carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy,cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino,substituted guanidino, halo, hydroxy, hydroxyamino, alkoxyamino,hydrazino, substituted hydrazino, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, oxo, thione, spirocycloalkyl, SO₃H, substitutedsulfonyl, sulfonyloxy, thioacyl, thiocyanate, thiol, alkylthio, andsubstituted alkylthio, wherein said substituents are as defined herein.

“Alkenyl” refers to a linear or branched hydrocarbyl group having from 2to 10 carbon atoms and in some embodiments from 2 to 6 carbon atoms or 2to 4 carbon atoms and having at least 1 site of vinyl unsaturation(>C═C<). For example, (C_(u-v))alkenyl refers to alkenyl groups havingfrom u to v carbon atoms and is meant to include for example, ethenyl,propenyl, 1,3-butadienyl, and the like.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 3substituents and, in some embodiments, 1 to 2 substituents, selectedfrom the group consisting of alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, alkyl, substituted alkyl, alkynyl, substitutedalkynyl, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,substituted aryl, aryloxy, substituted aryloxy, arylthio, substitutedarylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,substituted heteroarylthio, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are defined as herein and with the provisothat any hydroxy or thiol substitution is not attached to an acetyleniccarbon atom.

“Alkynyl” refers to a linear monovalent hydrocarbon radical or abranched monovalent hydrocarbon radical containing at least one triplebond. The term “alkynyl” is also meant to include those hydrocarbylgroups having one triple bond and one double bond. For example,(C₂-C₆)alkynyl is meant to include ethynyl, propynyl, and the like.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 3substituents and, in some embodiments, from 1 to 2 substituents,selected from the group consisting of alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminocarbonyl,aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino,amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio,substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino,(carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substitutedcycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy,substituted cycloalkenyloxy, cycloalkenylthio, substitutedcycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy,heteroaryl, substituted heteroaryl, heteroaryloxy, substitutedheteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic,substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substitutedsulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substitutedalkylthio, wherein said substituents are defined herein and with theproviso that any hydroxy or thiol substitution is not attached to anacetylenic carbon atom.

“Alkoxy” refers to the group —O-alkyl wherein alkyl is defined herein.Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

“Substituted alkoxy” refers to the group —O-(substituted alkyl) whereinsubstituted alkyl is as defined herein.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, substitutedhydrazino-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—,heterocyclic-C(O)—, and substituted heterocyclic-C(O)—, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,substituted hydrazino, heteroaryl, substituted heteroaryl, heterocyclicand substituted heterocyclic are as defined herein. Acyl includes the“acetyl” group CH₃C(O)—.

“Acylamino” refers to the groups —NR²⁰C(O)H, —NR²⁰C(O)alkyl,—NR²⁰C(O)substituted alkyl, —NR²⁰C(O)cycloalkyl, —NR²⁰C(O)substitutedcycloalkyl, —NR²⁰C(O)alkenyl, —NR²⁰C(O)substituted alkenyl,—NR²⁰C(O)alkynyl, —NR²⁰C(O)substituted alkynyl, —NR²⁰C(O)aryl,—NR²⁰C(O)substituted aryl, —NR²⁰C(O)heteroaryl, —NR²⁰C(O)substitutedheteroaryl, —NR²⁰C(O)heterocyclic, and —NR²⁰C(O)substituted heterocyclicwherein R²⁰ is hydrogen or alkyl and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Acyloxy” refers to the groups H—C(O)O—, alkyl-C(O)O—, substitutedalkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl-C(O)O—, substitutedaryl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—,and substituted heterocyclic-C(O)O— wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR²¹R²² where R²¹ and R²² areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl,—SO₂-substituted alkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl,—SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substitutedheteroaryl, —SO₂-heterocyclyl, and —SO₂-substituted heterocyclyl andwherein R²¹ and R²² are optionally joined together with the nitrogenbound thereto to form a heterocyclyl or substituted heterocyclyl group,provided that R²¹ and R²² are both not hydrogen, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein. When R²¹ is hydrogen and R²² isalkyl, the substituted amino group is sometimes referred to herein asalkylamino. When R²¹ and R²² are alkyl, the substituted amino group issometimes referred to herein as dialkylamino. When referring to amonosubstituted amino, it is meant that either R²¹ or R²² is hydrogenbut not both. When referring to a disubstituted amino, it is meant thatneither R²¹ nor R²² are hydrogen.

“Hydroxyamino” refers to the group —NHOH.

“Alkoxyamino” refers to the group —NHO-alkyl wherein alkyl is definedherein.

“Aminocarbonyl” refers to the group —C(O)NR²³R²⁴ where R²³ and R²⁴ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, hydroxy, alkoxy, substituted alkoxy, amino, substitutedamino, and acylamino, and where R²³ and R²⁴ are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminothiocarbonyl” refers to the group —C(S)NR²³R²⁴ where R²³ and R²⁴are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic and where R²³ and R²⁴ are optionally joined together withthe nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminocarbonylamino” refers to the group —NR²⁰C(O)NR²³R²⁴ where R²⁰ ishydrogen or alkyl and R²³ and R²⁴ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²³ andR²⁴ are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminothiocarbonylamino” refers to the group —NR²⁰C(S)NR²³R²⁴ where R²⁰is hydrogen or alkyl and R²³ and R²⁴ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²³ andR²⁴ are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminocarbonyloxy” refers to the group —O—C(O)NR²³R²⁴ where R²³ and R²⁴are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic and where R²³ and R²⁴ are optionally joined together withthe nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminosulfonyl” refers to the group —SO₂NR²³R²⁴ where R²³ and R²⁴ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic and where R²³ and R²⁴ are optionally joined together withthe nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminosulfonyloxy” refers to the group —O—SO₂NR²³R²⁴ where R²³ and R²⁴are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic and where R²³ and R²⁴ are optionally joined together withthe nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminosulfonylamino” refers to the group —NR²⁰—SO₂NR²³R²⁴ where R²⁰ ishydrogen or alkyl and R²³ and R²⁴ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²³ andR²⁴ are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Amidino” refers to the group —C(═NR²⁵)NR²³R²⁴ where R²⁵, R²³, and R²⁴are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic and where R²³ and R²⁴ are optionally joined together withthe nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aryl” refers to an aromatic group of from 6 to 14 carbon atoms and noring heteroatoms and having a single ring (e.g., phenyl) or multiplecondensed (fused) rings (e.g., naphthyl or anthryl). For multiple ringsystems, including fused, bridged, and spiro ring systems havingaromatic and non-aromatic rings that have no ring heteroatoms, the term“Aryl” or “Ar” applies when the point of attachment is at an aromaticcarbon atom (e.g., 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl groupas its point of attachment is at the 2-position of the aromatic phenylring).

“Substituted aryl” refers to aryl groups which are substituted with 1 to8 and, in some embodiments, 1 to 5, 1 to 3 or 1 to 2 substituentsselected from the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substitutedalkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido,carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy,cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino,substituted guanidino, halo, hydroxy, hydroxyamino, alkoxyamino,hydrazino, substituted hydrazino, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy,thioacyl, thiocyanate, thiol, alkylthio, and substituted alkylthio,wherein said substituents are defined herein.

“Arylalkyl” or “Aryl(C₁-C_(z))alkyl” refers to the radical —R^(u)R^(v)where R^(u) is an alkylene group (having eight or fewer main chaincarbon atoms) and R^(v) is an aryl group as defined herein. Thus,“arylalkyl” refers to groups such as, for example, benzyl, andphenylethyl, and the like. Similarly, “Arylalkenyl” means a radical—R^(u)R^(v) where R^(u) is an alkenylene group (an alkylene group havingone or two double bonds) and R^(v) is an aryl group as defined herein,e.g., styrenyl, 3-phenyl-2-propenyl, and the like.

“Aryloxy” refers to the group —O-aryl, where aryl is as defined herein,that includes, by way of example, phenoxy and naphthoxy.

“Substituted aryloxy” refers to the group —O-(substituted aryl) wheresubstituted aryl is as defined herein.

“Arylthio” refers to the group-S-aryl, where aryl is as defined herein.

“Substituted arylthio” refers to the group —S-(substituted aryl), wheresubstituted aryl is as defined herein.

“Azido” refers to the group —N₃.

“Hydrazino” refers to the group —NHNH₂.

“Substituted hydrazino” refers to the group —NR²⁶NR²⁷R²⁸ where R²⁶, R²⁷,and R²⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, carboxyl ester,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —SO₂-alkyl, —SO₂-substitutedalkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-cycloalkyl,—SO₂-substituted cycloalkyl, —SO₂-aryl, —SO₂-substituted aryl,—SO₂-heteroaryl, —SO₂-substituted heteroaryl, —SO₂-heterocyclic, and—SO₂-substituted heterocyclic and wherein R²⁷ and R²⁸ are optionallyjoined, together with the nitrogen bound thereto to form a heterocyclicor substituted heterocyclic group, provided that R²⁷ and R²⁸ are bothnot hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein.

“Cyano” or “carbonitrile” refers to the group —CN.

“Carbonyl” refers to the divalent group —C(O)— which is equivalent to—C(═O)—.

“Carboxyl” or “carboxy” refers to —COOH or salts thereof.

“Carboxyl ester” or “carboxy ester” refers to the groups —C(O)O-alkyl,—C(O)O-substituted alkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl,—C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)β-cycloalkyl, —C(O)O-substitutedcycloalkyl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl,—C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein.

“(Carboxyl ester)amino” refers to the group —NR²⁰—C(O)O-alkyl,—NR²⁰—C(O)O-substituted alkyl, —NR²⁰—C(O)O-alkenyl,—NR²⁰—C(O)O-substituted alkenyl, —NR²⁰—C(O)O-alkynyl,—NR²⁰—C(O)O-substituted alkynyl, —NR²⁰—C(O)O-aryl,—NR²⁰—C(O)O-substituted aryl, —NR²⁰—C(O)β-cycloalkyl,—NR²⁰—C(O)O-substituted cycloalkyl, —NR²⁰—C(O)O-heteroaryl,—NR²⁰—C(O)O-substituted heteroaryl, —NR²⁰—C(O)O-heterocyclic, and—NR²⁰—C(O)O-substituted heterocyclic wherein R²⁰ is alkyl or hydrogen,and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“(Carboxyl ester)oxy” refers to the group —O—C(O)O-alkyl,—O—C(O)O-substituted alkyl, —O—C(O)O-alkenyl, —O—C(O)O-substitutedalkenyl, —O—C(O)O-alkynyl, —O—C(O)O-substituted alkynyl, —O—C(O)O-aryl,—O—C(O)O-substituted aryl, —O—C(O)β-cycloalkyl, —O—C(O)O-substitutedcycloalkyl, —O—C(O)O-heteroaryl, —O—C(O)O-substituted heteroaryl,—O—C(O)O-heterocyclic, and —O—C(O)O-substituted heterocyclic whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“Cycloalkyl” refers to a saturated or partially saturated cyclic groupof from 3 to 14 carbon atoms and no ring heteroatoms and having a singlering or multiple rings including fused, bridged, and spiro ring systems.For multiple ring systems having aromatic and non-aromatic rings thathave no ring heteroatoms, the term “cycloalkyl” applies when the pointof attachment is at a non-aromatic carbon atom (e.g.,5,6,7,8,-tetrahydronaphthalene-5-yl). The term “cycloalkyl” includescycloalkenyl groups. Examples of cycloalkyl groups include, forinstance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl,and cyclohexenyl. “C_(u-v)cycloalkyl” refers to cycloalkyl groups havingu to v carbon atoms as ring members. “C_(u-v)cycloalkenyl” refers tocycloalkenyl groups having u to v carbon atoms as ring members.

“Cycloalkenyl” refers to a partially saturated cycloalkyl ring having atleast one site of >C═C< ring unsaturation.

“Substituted cycloalkyl” refers to a cycloalkyl group, as definedherein, having from 1 to 8, or 1 to 5, or in some embodiments 1 to 3substituents selected from the group consisting of oxo, thione, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido,carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy,cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino,substituted guanidino, halo, hydroxy, hydroxyamino, alkoxyamino,hydrazino, substituted hydrazino, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy,thioacyl, thiocyanate, thiol, alkylthio, and substituted alkylthio,wherein said substituents are as defined herein. The term “substitutedcycloalkyl” includes substituted cycloalkenyl groups.

“Cycloalkyloxy” refers to —O-cycloalkyl wherein cycloalkyl is as definedherein.

“Substituted cycloalkyloxy” refers to —O-(substituted cycloalkyl)wherein substituted cycloalkyl is as defined herein.

“Cycloalkylthio” refers to —S-cycloalkyl wherein substituted cycloalkylis as defined herein.

“Substituted cycloalkylthio” refers to —S-(substituted cycloalkyl)wherein substituted cycloalkyl is as defined herein.

“Guanidino” refers to the group —NHC(═NH)NH₂.

“Substituted guanidino” refers to —NR²⁹C(═NR²⁹)N(R²⁹)₂ where each R²⁹ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl and two R²⁹groups attached to a common guanidino nitrogen atom are optionallyjoined together with the nitrogen bound thereto to form a heterocyclicor substituted heterocyclic group, provided that at least one R²⁹ is nothydrogen, and wherein said substituents are as defined herein.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

“Haloalkyl” refers to substitution of alkyl groups with 1 to 5 or insome embodiments 1 to 3 halo groups, e.g., —CH₂Cl, —CH₂F, —CH₂Br,—CFClBr, —CH₂CH₂Cl, —CH₂CH₂F, —CF₃, —CH₂CF₃, —CH₂CCl₃, and the like, andfurther includes those alkyl groups such as perfluoroalkyl in which allhydrogen atoms are replaced by fluorine atoms.

“Haloalkoxy” refers to substitution of alkoxy groups with 1 to 5 or insome embodiments 1 to 3 halo groups, e.g., —OCH₂Cl, —OCH₂F, —OCH₂CH₂Br,—OCH₂CH₂Cl, —OCF₃, and the like.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroalkyl” means an alkyl radical as defined herein with one, two orthree substituents independently selected from cyano, —OR^(w),—NR^(x)R^(y), and —S(O)_(n)R^(z) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom of the heteroalkyl radical. R^(w) ishydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl,alkoxycarbonyl, aryloxycarbonyl, carboxamido, or mono- ordi-alkylcarbamoyl. R^(x) is hydrogen, alkyl, cycloalkyl,cycloalkyl-alkyl, aryl or arylalkyl. R^(y) is hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkoxycarbonyl,aryloxycarbonyl, carboxamido, mono- or di-alkylcarbamoyl oralkylsulfonyl. R^(z) is hydrogen (provided that n is 0), alkyl,cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, amino, mono-alkylamino,di-alkylamino, or hydroxyalkyl. Representative examples include, forexample, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2-methoxyethyl,benzyloxymethyl, 2-cyanoethyl, and 2-methylsulfonyl-ethyl. For each ofthe above, R^(w), R^(x), R^(y), and R^(z) can be further substituted byamino, fluorine, alkylamino, di-alkylamino, OH or alkoxy. Additionally,the prefix indicating the number of carbon atoms (e.g., C₁-C₁₀) refersto the total number of carbon atoms in the portion of the heteroalkylgroup exclusive of the cyano, —OR^(w), —NR^(x)R^(y), or —S(O)_(n)R^(z)portions.

“Heteroaryl” refers to an aromatic group of from 1 to 14 carbon atomsand 1 to 6 heteroatoms selected from the group consisting of oxygen,nitrogen, and sulfur and includes a 5 to 18 member ring or ring systemthat includes a single ring (e.g., imidazolyl) or multiple rings (e.g.,benzimidazol-2-yl and benzimidazol-6-yl). For multiple ring systems,including fused, bridged, and spiro ring systems having aromatic andnon-aromatic rings, the term “heteroaryl” applies if there is at leastone ring heteroatom and the point of attachment is at an atom of anaromatic ring (e.g., 1,2,3,4-tetrahydroquinolin-6-yl and5,6,7,8-tetrahydroquinolin-3-yl). In one embodiment, the nitrogen and/orthe sulfur ring atom(s) of the heteroaryl group are optionally oxidizedto provide for the N-oxide (N→O), sulfinyl, or sulfonyl moieties. Morespecifically the term heteroaryl includes, but is not limited to,pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl,imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl,benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl,benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl,quinolyl, tetrahydroquinolinyl, isoquinolyl, quinazolinonyl,benzimidazolyl, benzisoxazolyl, or benzothienyl.

“Substituted heteroaryl” refers to heteroaryl groups that aresubstituted with from 1 to 8, or in some embodiments 1 to 5, or 1 to 3,or 1 to 2 substituents selected from the group consisting of thesubstituents defined for substituted aryl.

“Heteroaryloxy” refers to —O-heteroaryl wherein heteroaryl is as definedherein.

“Substituted heteroaryloxy” refers to the group —O-(substitutedheteroaryl) wherein heteroaryl is as defined herein.

“Heteroarylthio” refers to the group —S-heteroaryl wherein heteroaryl isas defined herein.

“Substituted heteroarylthio” refers to the group —S-(substitutedheteroaryl) wherein heteroaryl is as defined herein.

“Heterocycle” or “heterocyclic” or “heterocyclo” or “heterocycloalkyl”or “heterocyclyl” refers to a saturated or partially saturated cyclicgroup having from 1 to 14 carbon atoms and from 1 to 6 heteroatomsselected from the group consisting of nitrogen, sulfur, or oxygen andincludes single ring and multiple ring systems including fused, bridged,and spiro ring systems. For multiple ring systems having aromatic and/ornon-aromatic rings, the term “heterocyclic”, “heterocycle”,“heterocyclo”, “heterocycloalkyl” or “heterocyclyl” applies when thereis at least one ring heteroatom and the point of attachment is at anatom of a non-aromatic ring (e.g., 1,2,3,4-tetrahydroquinoline-3-yl,5,6,7,8-tetrahydroquinoline-6-yl, and decahydroquinolin-6-yl). In oneembodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic groupare optionally oxidized to provide for the N-oxide, sulfinyl, sulfonylmoieties. More specifically the heterocyclyl includes, but is notlimited to, tetrahydropyranyl, piperidinyl, N-methylpiperidin-3-yl,piperazinyl, N-methylpyrrolidin-3-yl, 3-pyrrolidinyl, 2-pyrrolidon-1-yl,morpholinyl, and pyrrolidinyl. A prefix indicating the number of carbonatoms (e.g., C₃-C₁₀) refers to the total number of carbon atoms in theportion of the heterocyclyl group exclusive of the number ofheteroatoms.

“Substituted heterocycle” or “substituted heterocyclic” or “substitutedheterocyclo” or “substituted heterocycloalkyl” or “substitutedheterocyclyl” refers to heterocyclic groups, as defined herein, that aresubstituted with from 1 to 5 or in some embodiments 1 to 3 of thesubstituents as defined for substituted cycloalkyl.

“Heterocyclyloxy” refers to the group —O-heterocyclyl whereinheterocyclyl is as defined herein.

“Substituted heterocyclyloxy” refers to the group —O-(substitutedheterocyclyl) wherein heterocyclyl is as defined herein.

“Heterocyclylthio” refers to the group —S-heterocycyl whereinheterocyclyl is as defined herein.

“Substituted heterocyclylthio” refers to the group —S-(substitutedheterocycyl) wherein heterocyclyl is as defined herein.

Examples of heterocycle and heteroaryl groups include, but are notlimited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,and tetrahydrofuranyl.

“Nitro” refers to the group —NO₂.

“Oxo” refers to the atom (═O).

“Oxide” refers to products resulting from the oxidation of one or moreheteroatoms. Examples include N-oxides, sulfoxides, and sulfones.

“Spirocycloalkyl” refers to a 3 to 10 member cyclic substituent formedby replacement of two hydrogen atoms at a common carbon atom with analkylene group having 2 to 9 carbon atoms, as exemplified by thefollowing structure wherein the methylene group shown below attached tobonds marked with wavy lines is substituted with a spirocycloalkylgroup:

“Sulfonyl” refers to the divalent group —S(O)₂—.

“Substituted sulfonyl” refers to the group —SO₂-alkyl, —SO₂-substitutedalkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-alkynyl,—SO₂-substituted alkynyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl,—SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substitutedheteroaryl, —SO₂-heterocyclic, —SO₂-substituted heterocyclic, whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein. Substituted sulfonylincludes groups such as methyl-SO₂—, phenyl-SO₂—, and4-methylphenyl-SO₂—.

“Sulfonyloxy” refers to the group —OSO₂-alkyl, —OSO₂-substituted alkyl,—OSO₂-alkenyl, —OSO₂-substituted alkenyl, —OSO₂-cycloalkyl,—OSO₂-substituted cycloalkyl, —OSO₂-aryl, —OSO₂-substituted aryl,—OSO₂-heteroaryl, —OSO₂-substituted heteroaryl, —OSO₂-heterocyclic,—OSO₂-substituted heterocyclic, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Thioacyl” refers to the groups H—C(S)—, alkyl-C(S)—, substitutedalkyl-C(S)—, alkenyl-C(S)—, substituted alkenyl-C(S)—, alkynyl-C(S)—,substituted alkynyl-C(S)—, cycloalkyl-C(S)—, substitutedcycloalkyl-C(S)—, aryl-C(S)—, substituted aryl-C(S)—, heteroaryl-C(S)—,substituted heteroaryl-C(S)—, heterocyclic-C(S)—, and substitutedheterocyclic-C(S)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Thiol” refers to the group —SH.

“Alkylthio” refers to the group —S-alkyl wherein alkyl is as definedherein.

“Substituted alkylthio” refers to the group —S-(substituted alkyl)wherein substituted alkyl is as defined herein.

“Thiocarbonyl” refers to the divalent group —C(S)— which is equivalentto —C(═S)—.

“Thione” refers to the atom (═S).

“Thiocyanate” refers to the group —SCN.

“Compound” and “compounds” as used herein refers to a compoundencompassed by the generic formulae disclosed herein, any subgenus ofthose generic formulae, and any forms of the compounds within thegeneric and subgeneric formulae, such as an oxide, ester, prodrug,pharmaceutically acceptable salt, or solvate. Unless specifiedotherwise, the term further includes the racemates, stereoisomers, andtautomers of the compound or compounds.

“Racemates” refers to a mixture of enantiomers.

“Solvate” or “solvates” of a compound refer to those compounds, wherecompounds are as defined above, that are bound to a stoichiometric ornon-stoichiometric amount of a solvent. Solvates of a compound includessolvates of all forms of the compound such as the oxide, ester, prodrug,or pharmaceutically acceptable salt of the disclosed generic andsubgeneric formulae. Preferred solvents are volatile, non-toxic, and/oracceptable for administration to humans.

“Stereoisomer” or “stereoisomers” refer to compounds that differ in thechirality of one or more stereocenters. Stereoisomers includeenantiomers and diastereomers. The compounds of this invention may existin stereoisomeric form if they possess one or more asymmetric centers ora double bond with asymmetric substitution and, therefore, can beproduced as individual stereoisomers or as mixtures. Unless otherwiseindicated, the description is intended to include individualstereoisomers as well as mixtures. The methods for the determination ofstereochemistry and the separation of stereoisomers are well-known inthe art (see discussion in Chapter 4 of Advanced Organic Chemistry, 4thedition J. March, John Wiley and Sons, New York, 1992).

“Tautomer” refers to alternate forms of a compound that differ in theposition of a proton, such as enol-keto and imine-enamine tautomers, orthe tautomeric forms of heteroaryl groups containing a ring atomattached to both a ring —NH— moiety and a ring ═N— moiety such aspyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

“Prodrug” refers to any derivative of a compound of the embodiments thatis capable of directly or indirectly providing a compound of theembodiments or an active metabolite or residue thereof when administeredto a patient. Prodrugs of a compound of the present invention areprepared by modifying functional groups present in the compound in sucha way that the modifications may be cleaved in vivo to release theparent compound, or an active metabolite. For example, prodrugs includecompounds wherein a hydroxy, amino, or sulfhydryl group in a compound Iis bonded to any group that may be cleaved in vivo to regenerate thefree hydroxyl, amino, or sulfhydryl group, respectively. Particularlyfavored derivatives and prodrugs are those that increase thebioavailability of the compounds of the embodiments when such compoundsare administered to a patient (e.g., by allowing an orally administeredcompound to be more readily absorbed into the blood) or which enhancedelivery of the parent compound to a biological compartment (e.g., thebrain or lymphatic system) relative to the parent species. Prodrugsinclude ester, amide, carbamate (e.g., N,N-dimethylaminocarbonyl) formsof hydroxy functional groups of compounds of the invention. Examples ofester prodrugs include formate, acetate, propionate, butyrate, acrylate,and ethylsuccinate derivatives. An general overview of prodrugs isprovided in T Higuchi and V Stella, Pro-drugs as Novel Delivery Systems,Vol. 14 of the A.C.S. Symposium Series, and in Edward B Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts derived from a variety of organic and inorganic counter ions wellknown in the art and include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, and tetraalkylammonium. When the moleculecontains a basic functionality, acid addition salts of organic orinorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like; or formed with organicacids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, oxalic acid, 4-toluenesulfonic acid,camphorsulfonic acid, methanesulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like. Saltscan also be formed when an acidic proton present in the parent compoundis either replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,trimethylamine, N-methylglucamine, and the like. Pharmaceuticallyacceptable salts are suitable for administration in a patient andpossess desirable pharmacological properties. Suitable salts furtherinclude those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.),Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“arylalkyloxycabonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,which is further substituted by a substituted aryl group, etc.) are notintended for inclusion herein. In such cases, the maximum number of suchsubstitutions is three. For example, serial substitutions of substitutedaryl groups with two other substituted aryl groups are limited to-substituted aryl-(substituted aryl)-substituted aryl.

Similarly, it is understood that the above definitions are not intendedto include impermissible substitution patterns (e.g., methyl substitutedwith 5 fluoro groups). Such impermissible substitution patterns are wellknown to the skilled artisan.

“Patient” refers to mammals and includes humans and non-human mammals.Examples of patients include, but are not limited to mice, rats,hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows,and humans.

The term “mammal” includes, without limitation, humans, domestic animals(e.g., dogs or cats), farm animals (cows, horses, or pigs), andlaboratory animals (mice, rats, hamsters, guinea pigs, pigs, rabbits,dogs, or monkeys).

The terms “optional” or “optionally” as used throughout thespecification means that the subsequently described event orcircumstance may but need not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, “heterocyclo group optionally mono- ordi-substituted with an alkyl group” means that the alkyl may but neednot be present, and the description includes situations where theheterocyclo group is mono- or disubstituted with an alkyl group andsituations where the heterocyclo group is not substituted with the alkylgroup.

“Protecting group” refers to a grouping of atoms that when attached to areactive group in a molecule masks, reduces or prevents that reactivity.Examples of protecting groups can be found in T. W. Greene and P. G.Wuts, Protective Groups in Organic Chemistry, (Wiley, 2nd ed. 1991) andHarrison and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8 (John Wiley and Sons. 1971-1996). Representative aminoprotecting groups include formyl, acetyl, trifluoroacetyl, benzyl,benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl(TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substitutedtrityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC),nitro-veratryloxycarbonyl (NVOC) and the like. Representative hydroxyprotecting groups include those where the hydroxy group is eitheracylated or alkylated such as benzyl and trityl ethers as well as alkylethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

Turning next to the compositions of the invention, the term“pharmaceutically acceptable carrier or excipient” means a carrier orexcipient that is useful in preparing a pharmaceutical composition thatis generally safe, possesses acceptable toxicities. Acceptable carriersor excipients include those that are acceptable for veterinary use aswell as human pharmaceutical use. A “pharmaceutically acceptable carrieror excipient” as used in the specification and claims includes both oneand more than one such carrier or excipient.

With reference to the methods of the present invention, the followingterms are used with the noted meanings

The terms “treating” or “treatment” of a disease includes:

(1) preventing or reducing the risk of developing the disease, i.e.,causing the clinical symptoms of the disease not to develop in a mammalthat may be exposed to or predisposed to the disease but does not yetexperience or display symptoms of the disease,

(2) inhibiting the disease, i.e., arresting or reducing the developmentof the disease or its clinical symptoms, or

(3) relieving the disease, i.e., causing regression of the disease orits clinical symptoms.

A preferred embodiment of the invention is treatment of a disease thatconsists of relieving the disease.

The term “diagnosing” refers to determining the presence or absence of aparticular disease or condition. Additionally, the term refers todetermining the level or severity of a particular disease or condition,as well as monitoring of the disease or condition to determine itsresponse to a particular therapeutic regimen.

The term “therapeutically effective amount” means the amount of thesubject compound that will elicit the biological or medical response ofa tissue, system, animal or human that is being sought by theresearcher, veterinarian, medical doctor or other clinician. “Atherapeutically effective amount” includes the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

“Patient” refers to mammals and includes humans and non-human mammals.Examples of patients include, but are not limited to mice, rats,hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows,and humans.

The term “mammal” includes, without limitation, humans, domestic animals(e.g., dogs or cats), farm animals (cows, horses, or pigs), andlaboratory animals (mice, rats, hamsters, guinea pigs, pigs, rabbits,dogs, or monkeys).

The term “insulin resistance” can be defined generally as a disorder ofglucose metabolism. More specifically, insulin resistance can be definedas the diminished ability of insulin to exert its biological actionacross a broad range of concentrations producing less than the expectedbiologic effect (see, e.g., Reaven G M, J. Basic & Clin. Phys. & Pharm.(1998) 9:387-406 and Flie J, Ann Rev. Med. (1983) 34:145-60). Insulinresistant persons have a diminished ability to properly metabolizeglucose and respond poorly, if at all, to insulin therapy.Manifestations of insulin resistance include insufficient insulinactivation of glucose uptake, oxidation and storage in muscle andinadequate insulin repression of lipolysis in adipose tissue and ofglucose production and secretion in liver. Insulin resistance can causeor contribute to polycystic ovarian syndrome, impaired glucosetolerance, gestational diabetes, metabolic syndrome, hypertension,obesity, atherosclerosis and a variety of other disorders. Eventually,the insulin resistant individuals can progress to a point where adiabetic state is reached.

The term “diabetes mellitus” or “diabetes” means a disease or conditionthat is generally characterized by metabolic defects in production andutilization of glucose that result in the failure to maintainappropriate blood sugar levels in the body. The result of these defectsis elevated blood glucose, referred to as “hyperglycemia.” Two majorforms of diabetes are Type I diabetes and Type II diabetes. As describedabove, Type I diabetes is generally the result of an absolute deficiencyof insulin, the hormone that regulates glucose utilization. Type IIdiabetes often occurs in the face of normal, or even elevated levels ofinsulin and can result from the inability of tissues to respondappropriately to insulin. Most Type II diabetic patients are insulinresistant and have a relative deficiency of insulin, in that insulinsecretion can not compensate for the resistance of peripheral tissues torespond to insulin. In addition, many Type II diabetics are obese. Othertypes of disorders of glucose homeostasis include impaired glucosetolerance, which is a metabolic stage intermediate between normalglucose homeostasis and diabetes, and gestational diabetes mellitus,which is glucose intolerance in pregnancy in women with no previoushistory of Type I or Type II diabetes.

The term “metabolic syndrome” refers to a cluster of metabolicabnormalities including abdominal obesity, insulin resistance, glucoseintolerance, diabetes, hypertension and dyslipidemia. Theseabnormalities are known to be associated with an increased risk ofvascular events.

The term “abdominal obesity” is defined by a cutoff point of waistcircumference≧102 cm in men and ≧80 cm in women, as recommended by thethird report of the national cholesterol education program expert panelon detection, evaluation, and treatment of high blood cholesterol inadults (NCEP/ATP Panel III).

The guidelines for diagnosis of Type II diabetes, impaired glucosetolerance, and gestational diabetes have been outlined by the AmericanDiabetes Association (see, e.g., The Expert Committee on the Diagnosisand Classification of Diabetes Mellitus, Diabetes Care, (1999) Vol 2(Suppl 1):S5-19).

The term “secretagogue” means a substance or compound that stimulatessecretion. For example, an insulin secretagogue is a substance orcompound that stimulates secretion of insulin.

The term “symptom” of diabetes, includes, but is not limited to,polyuria, polydipsia, and polyphagia, as used herein, incorporatingtheir common usage. For example, “polyuria” means the passage of a largevolume of urine during a given period; “polydipsia” means chronic,excessive thirst; and “polyphagia” means excessive eating. Othersymptoms of diabetes include, e.g., increased susceptibility to certaininfections (especially fungal and staphylococcal infections), nausea,and ketoacidosis (enhanced production of ketone bodies in the blood).

The term “complication” of diabetes includes, but is not limited to,microvascular complications and macrovascular complications.Microvascular complications are those complications that generallyresult in small blood vessel damage. These complications include, e.g.,retinopathy (the impairment or loss of vision due to blood vessel damagein the eyes); neuropathy (nerve damage and foot problems due to bloodvessel damage to the nervous system); and nephropathy (kidney diseasedue to blood vessel damage in the kidneys). Macrovascular complicationsare those complications that generally result from large blood vesseldamage. These complications include, e.g., cardiovascular disease andperipheral vascular disease. Cardiovascular disease refers to diseasesof blood vessels of the heart. See, e.g., Kaplan R M, et al.,“Cardiovascular diseases” in Health and Human Behavior, pp. 206-242(McGraw-Hill, New York 1993). Cardiovascular disease is generally one ofseveral forms, including, e.g., hypertension (also referred to as highblood pressure), coronary heart disease, stroke, and rheumatic heartdisease. Peripheral vascular disease refers to diseases of any of theblood vessels outside of the heart. It is often a narrowing of the bloodvessels that carry blood to leg and arm muscles.

The term “atherosclerosis” encompasses vascular diseases and conditionsthat are recognized and understood by physicians practicing in therelevant fields of medicine. Atherosclerotic cardiovascular disease,coronary heart disease (also known as coronary artery disease orischemic heart disease), cerebrovascular disease and peripheral vesseldisease are all clinical manifestations of atherosclerosis and aretherefore encompassed by the terms “atherosclerosis” and“atherosclerotic disease”.

The term “antihyperlipidemic” refers to the lowering of excessive lipidconcentrations in blood to desired levels.

The term “modulate” refers to the treating, prevention, suppression,enhancement or induction of a function or condition. For example,compounds can modulate Type II diabetes by increasing insulin in ahuman, thereby suppressing hyperglycemia.

The term “triglyceride(s)” (“TGs”), as used herein, incorporates itscommon usage. TGs consist of three fatty acid molecules esterified to aglycerol molecule. TGs serve to store fatty acids that are used bymuscle cells for energy production or are taken up and stored in adiposetissue.

Because cholesterol and TGs are water insoluble, they must be packagedin special molecular complexes known as “lipoproteins” in order to betransported in the plasma. Lipoproteins can accumulate in the plasma dueto overproduction and/or deficient removal. There are at least fivedistinct lipoproteins differing in size, composition, density, andfunction. In the cells of the small intestine, dietary lipids arepackaged into large lipoprotein complexes called “chylomicrons”, whichhave a high TG and low-cholesterol content. In the liver, TG andcholesterol esters are packaged and released into plasma as TG-richlipoprotein called very low density lipoprotein (“VLDL”), whose primaryfunction is the endogenous transport of TGs made in the liver orreleased by adipose tissue. Through enzymatic action, VLDL can be eitherreduced and taken up by the liver, or transformed into intermediatedensity lipoprotein (“IDL”). IDL, is in turn, either taken up by theliver, or is further modified to form low density lipoprotein (“LDL”).LDL is either taken up and broken down by the liver, or is taken up byextrahepatic tissue. High density lipoprotein (“HDL”) helps removecholesterol from peripheral tissues in a process called reversecholesterol transport.

The term “dyslipidemia” refers to abnormal levels of lipoproteins inblood plasma including both depressed and/or elevated levels oflipoproteins (e.g., elevated levels of LDL and/or VLDL, and depressedlevels of HDL).

The term “hyperlipidemia” includes, but is not limited to, thefollowing:

(1) Familial Hyperchylomicronemia, a rare genetic disorder that causes adeficiency in an enzyme, LP lipase, that breaks down fat molecules. TheLP lipase deficiency can cause the accumulation of large quantities offat or lipoproteins in the blood;

(2) Familial Hypercholesterolemia, a relatively common genetic disordercaused where the underlying defect is a series of mutations in the LDLreceptor gene that result in malfunctioning LDL receptors and/or absenceof the LDL receptors. This brings about ineffective clearance of LDL bythe LDL receptors resulting in elevated LDL and total cholesterol levelsin the plasma;

(3) Familial Combined Hyperlipidemia, also known as multiplelipoprotein-type hyperlipidemia is an inherited disorder where patientsand their affected first-degree relatives can at various times manifesthigh cholesterol and high triglycerides. Levels of HDL cholesterol areoften moderately decreased;

(4) Familial Defective Apolipoprotein B-100 is a relatively commonautosomal dominant genetic abnormality. The defect is caused by a singlenucleotide mutation that produces a substitution of glutamine forarginine, which can cause reduced affinity of LDL particles for the LDLreceptor. Consequently, this can cause high plasma LDL and totalcholesterol levels;

(5) Familial Dysbetaliproteinemia, also referred to as Type IIIHyperlipoproteinemia, is an uncommon inherited disorder resulting inmoderate to severe elevations of serum TG and cholesterol levels withabnormal apolipoprotein E function. HDL levels are usually normal; and

(6) Familial Hypertriglyceridemia, is a common inherited disorder inwhich the concentration of plasma VLDL is elevated. This can cause mildto moderately elevated TG levels (and usually not cholesterol levels)and can often be associated with low plasma HDL levels.

Risk factors for hyperlipidemia include, but are not limited to, thefollowing: (1) disease risk factors, such as a history of Type Idiabetes, Type II diabetes, Cushing's syndrome, hypothyroidism andcertain types of renal failure; (2) drug risk factors, which include,birth control pills; hormones, such as estrogen, and corticosteroids;certain diuretics; and various 13 blockers; (3) dietary risk factorsinclude dietary fat intake per total calories greater than 40%;saturated fat intake per total calories greater than 10%; cholesterolintake greater than 300 mg per day; habitual and excessive alcohol use;and obesity.

The terms “obese” and “obesity” refers to, according to the World HealthOrganization, a Body Mass Index (“BMI”) greater than 27.8 kg/m² for menand 27.3 kg/m² for women (BMI equals weight (kg)/height (m²). Obesity islinked to a variety of medical conditions including diabetes andhyperlipidemia. Obesity is also a known risk factor for the developmentof Type II diabetes (See, e.g., Barrett-Conner E, Epidemol. Rev. (1989)11:172-181; and Knowler, et al., Am. J. Clin. Nutr. (1991)53:1543-1551).

The term “pancreas” refers to a gland organ in the digestive andendocrine system of vertebrates, including mammals. The pancreassecretes both digestive enzymes and hormones such as insulin, GLP-1 andGIP as well as other hormones.

The term “islet” or “islet of Langerhans” refers to endocrine cells ofthe pancreas that are grouped together in islets and secrete insulin andother hormones.

The term “beta cell” refers to cells found in the islet of Langerhansthat secrete insulin, amylin, and other hormones.

The term “endocrine cell” refers to cells that secrete hormones into theblood stream. Endocrine cells are found various glands and organ systemsof the body including the pancreas, intestines, and other organs.

The term “L cell” refers to gut endocrine cells that produce GLP-1.

The term “K cell” refers to gut endocrine cells that produce GIP.

The term “incretin” refers to a group of hormones that increases insulinsecretion in response to food intake. Incretins include GLP-1 and GIP.

The term “insulin” refers to a polypeptide hormone that regulatesglucose metabolism. Insulin binds to insulin receptors in insulinsensitive cells and mediates glucose uptake. Insulin is used to treatType I diabetes and may be used to treat Type II diabetes.

The term “GLP-1” or “glucagon-like peptide” is a peptide hormoneprimarily produced by L cells. GLP-1 increases insulin secretion,decrease glucagon secretion, increase beta cell mass and insulin geneexpression, inhibits acid secretion and gastric emptying in the stomach,and decreases food intake by increasing satiety.

The term “GIP” or “gastric inhibitory peptide” or “glucose dependentinsulinotropic polypeptide” refers to a peptide hormone producedprimarily by K cells. GIP stimulates insulin secretion. GIP also hassignificant effects on lipid metabolism.

The term “cAMP” or “cyclic AMP” or “cyclic adenosine monophosphate”refers to an intracellular signaling molecule involved in manybiological processes, including glucose and lipid metabolism.

The term “agonist” refers to a compound that binds to a receptor andtriggers a response in a cell. An agonist mimics the effect of anendogenous ligand, a hormone for example, and produces a physiologicalresponse similar to that produced by the endogenous ligand.

The term “partial agonist” refers to a compound that binds to a receptorand triggers a partial response in a cell. A partial agonist producesonly a partial physiological response of the endogenous ligand.

The present invention derives from the discovery of compounds that actas agonists of IC-GPCR2 (Seq. ID 1) using a cell-based screen. A stableCHO cell line expressing IC-GPCR2 under the control of the CMV promoterwas used and cAMP levels were measured in the cells using a homogeneoustime resolved fluorescence assay. With a parental CHO cell line as acontrol, increased cAMP levels could be measured and compoundsidentified that, like exanatide, raise cAMP in cells (see In VitroActivity Table in Biological Example 1). Since elevated intracellularcAMP levels in the beta cell increase insulin secretion in a glucosedependant manner (see Biological Examples 2 and 3), the presentinvention is useful for the treatment of, inter alia, Type II diabetesand other diseases associated with poor glycemic control. The novelagonists described in this invention are orally active (see BiologicalExample 3), providing a significant differentiating feature toexanatide. Additionally, the islet specific expression of the receptorfor the novel agonists of the present invention (see Biological Example4) also make the present invention useful for the diagnosis of, interalia, diabetes and other diseases associated with beta cell health.

Embodiments of the Invention Compounds

The compounds of the present invention are represented by Formula I:

wherein, the letters X, Y and Z are each independently selected from O,N, N(R³), S and C(R³) and at least one of X, Y and Z is selected from O,N, N(R³) and S. The subscript q is an integer of from 0 to 4; thesubscript r is an integer of from 0 to 3; the subscript s is an integerof from 0 to 3, and the sum of r+s is ≦4. The letter A is C(R⁴) or N; Lis —(CH₂)_(n)— wherein n is an integer of from 2 to 4 and at least oneCH₂ is replaced by O, N(R⁵), S, S(O) or S(O)₂, and any remaining CH₂ isoptionally substituted with one or two members selected from halogen,C₁₋₄ alkyl and C₁₋₄ haloalkyl. Ar is a 5- to 10-membered aryl orheteroaryl group, optionally substituted with from one to five R⁶substituents.

Turning next to the R groups, R¹ is a member selected from C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, C₃₋₇ cycloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,—X¹—COR^(a), —X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), —SO₂R^(a), a 4- to7-membered heterocyclo group, aryl and a 5- to 10-membered heteroarylgroup, wherein each of the heterocyclo group and the aryl and theheteroaryl group is optionally substituted with from one to foursubstituents independently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, C₃₋₇ cycloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl,heteroaryl, CN, NO₂, —OR^(a), —NR^(a)R^(b), —CO₂R^(a), —CONR^(a)R^(b),—NR^(a)COR^(b), —NR^(a)CO₂R^(b), —S(O)_(m)R^(a), —NR^(a)S(O)₂R^(b), and—SO₂NR^(a)R^(b); and X¹ is selected from the group consisting of a bond,—C(O)— and —C(O)—(CH₂)₁₋₄—, wherein the aliphatic portions of X¹ areoptionally substituted with one to three members selected from halogen,C₁₋₄ alkyl and C₁₋₄ haloalkyl.

Each R² is a member independently selected from halo, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₇ cycloalkyl, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),—OR^(a), —NR^(a)R^(b), —NR^(a)COR^(b), —SO₂R^(a) and —SO₂NR^(a)R^(b).

R³ is a member selected from hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₇ cycloalkyl, aryl and OR^(a).

R⁴ is a member selected from H, halo, C₁₋₆ alkyl, OR^(a) and CN.

R⁵ is a member selected from —R^(a), —COR^(a) and —SO₂R^(a).

Each R⁶ is independently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, C₃₋₇ cycloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, CN, NO₂,—OR^(a), —NR^(a)R^(b), —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),—NR^(a)COR^(b), —NR^(a)CO₂R^(b), —S(O)_(m)R^(a), —NR^(a)S(O)_(m)R^(b),—SO₂NR^(a)R^(b), a 4- to 7-membered heterocyclo group, aryl and a 5- to10-membered heteroaryl group, wherein the subscript m is an integer offrom 0 to 2 and each of the heterocyclo groups, the aryl and theheteroaryl groups are optionally substituted with from one to foursubstituents independently selected from halo, oxo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₇ cycloalkyl, CN, NO₂, —OR^(a), —NR^(a)R^(b), —CO₂R^(a),—CONR^(a)R^(b), —NR^(a)COR^(b), —NR^(a)CO₂R^(b), —S(O)_(m)R^(a),—N^(a)SO₂R^(b), and —SO₂NR^(a)R^(b).

For each of the above groups, each R^(a) and R^(b) is independentlyselected from hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl,heterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl, 5- to 6-memberedheteroaryl and arylC₁₋₄alkyl; and wherein the aliphatic portions of eachof R^(a) and R^(b) is optionally substituted with from one to threemembers selected from —OR^(a), —OC(O)N(R^(n))₂, —Sr^(n), —S(O)R^(n),—S(O)₂R^(n), —S(O)₂N(R^(n))₂, —NR^(n)S(O)₂R^(n), —C(O)N(R^(n))₂,—C(O)R^(n), —NR^(n)C(O)R^(n), —NR^(n)C(O)N(R^(n))₂, —CO₂R^(n),—NR^(n)CO₂R^(n), —CN, —NO₂, —N(R^(n))₂ and —NR^(n)S(O)₂N(R^(n))₂,wherein each R^(n) is independently hydrogen or an unsubstituted C₁₋₆alkyl; and wherein the aryl and heteroaryl portions are optionallysubstituted with from one to three members selected from halogen,—OR^(m), —OC(O)N(R^(m))₂, —SR^(m), —S(O)R^(m), —S(O)₂R^(m),—S(O)₂N(R^(m))₂, —NR^(m)S(O)₂R^(m), —C(O)N(R^(m))₂, —C(O)R^(m),—NR^(m)C(O)R^(m), —NR^(m)C(O)N(R^(m))₂, —CO₂R^(m), —NR^(m)CO₂R^(m), —CN,—NO₂, —N(R^(m))₂ and —NR^(m)S(O)₂N(R^(m))₂, wherein each R^(m) isindependently hydrogen or an unsubstituted C₁₋₆ alkyl.

The compounds provided herein also include any pharmaceuticallyacceptable salts of the compounds as well as any isotopically labeledisomers thereof. In general, the compounds useful in the methodsdescribed herein are those compound of the formula above, wherein themolecular weight of the compound is less than 1200, more preferably lessthan about 1000, still more preferably less than about 800 and stillmore preferably from about 200 to about 600.

The ring having X, Y and Z as ring members will, in one group ofembodiments, be a ring in which two of X, Y and Z are independentlyselected from O, N, N(R³) and S. In another group of embodiments, thering is one in which all three of X, Y and Z are independently selectedfrom O, N, N(R³) and S. One group of preferred rings are represented bythe formulae

wherein the wavy lines indicate the positions of attachment to either Lor to A.

In another group of embodiments, A is CR⁴.

For each of the above groups of embodiments, an additional set ofembodiments are those in which r is 1, s is 0 or 1, q is 0 to 2 and Aris phenyl, optionally substituted with from 1 to 3 R⁶ substituents.Still another set of embodiments are those in which r is 1, s is 0 or 1,q is 0 and Ar is selected from the group consisting of pyridyl,pyrimidinyl and pyrazinyl, each of which is optionally substituted withfrom 1 to 3 R⁶ substituents. Yet another set of embodiments are those inwhich r is 1, s is 0 or 1, q is 0 to 2, and n is 2. In still another setof embodiments, r is 1, s is 0 or 1, q is 0 to 2, n is 2 and one CH₂ isreplaced by 0.

In another group of embodiments of Formula I, r is 1; s is 0 or 1; q is0 to 2; n is 2 and one of CH₂ of L is replaced by O, S or N(R⁵); A isselected from CH, C(CH₃), CF and C(OH); and the ring having X, Y and Zas ring members is selected from thiazole, oxazole, thiadiazole andoxadiazole. Preferably, Ar is phenyl, optionally substituted with from 1to 3 R⁶ substituents. More preferably, Ar is substituted with from 1 to2 R⁶ substituents independently selected from the group consisting ofhalo, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, CN, NO₂, —OR^(a), —NR^(a)R^(b),—COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —NR^(a)COR^(b), —NR^(a)CO₂R^(b),—S(O)_(m)R^(a), —NR^(a)S(O)_(m)R^(b), —SO₂NR^(a)R^(b), a 4- to5-membered heterocyclo group, aryl, and a 5- to 6-membered heteroarylgroup. In some embodiments, each R⁶ is independently selected from thegroup consisting of halo, —OR^(a), —NR^(a)R^(b), —NR^(a)COR^(b),—NR^(a)CO₂R^(b), —S(O)_(m)R^(a), —NR^(a)S(O)_(m)R^(b), —SO₂NR^(a)R^(b),a 4- to 5-membered heterocyclo group, aryl, and a 5- to 6-memberedheteroaryl group. Within each of the groups of embodiments and preferredembodiments, one group of further preferred embodiments are those inwhich R¹ is a 5- to 10-membered heteroaryl group, and is optionallysubstituted with from one to two substituents independently selectedfrom halo, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₃₋₇ cycloalkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, aryl, heteroaryl, CN, NO₂, —OR^(a), —NR^(a)R^(b),—CO₂R^(a), —CONR^(a)R^(b), —NR^(a)COR^(b), —NR^(a)CO₂R^(b),—S(O)_(m)R^(a), —N^(a)S(O)₂R^(b), and —SO₂NR^(a)R^(b). Still furtherpreferred are those embodiments in which R¹ is a pyridine or pyrimidine,and is optionally substituted with from one to two substituentsindependently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₃₋₇cycloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, heteroaryl, CN, NO₂,—OR^(a), —NR^(a)R^(b), —CO₂R^(a), —CONR^(a)R^(b), —NR^(a)COR^(b),—NR^(a)CO₂R^(b), —S(O)_(m)R^(a), —N^(a)S(O)₂R^(b), and —SO₂NR^(a)R^(b).In still another group of embodiments, R¹ is selected from the groupconsisting of —X¹—COR^(a), —X¹—CO₂R^(a), —X¹—CONR^(a)R^(b) and—SO₂R^(a).

In another aspect, this invention provides a compound represented byFormula II.

Wherein the letters X, Y, and Z are each independently selected from thegroup consisting of O, N, S, and C(R³) and at least one of X, Y, and Zis O, N, NR⁸, or S; J, K, T, and U are each independently selected fromthe group consisting of C, and N; the subscript p is an integer of from0 to 4; and the subscript q is an integer of from 0 to 4.

In Formula II, R¹ is a member selected from the group consisting of H,C₁₋₁₀alkyl, C₁₋₁₀substituted alkyl, C₃₋₇cyclo alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, —X¹—COR^(a), —X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), SO₂R^(a), a4- to 7-membered heterocyclo group, aryl and a 5- to 10-memberedheteroaryl group, wherein each of said cycloalkyl group, heterocyclogroup, aryl group and heteroaryl group is optionally substituted withfrom 1 to 4 substituents independently selected from halo, C₁₋₁₀alkyl,C₁₋₁₀substituted alkyl, C₃₋₇cycloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl,aryl, heteroaryl, CN, —NR^(a)COR^(b), —NR^(a)CONR^(a)R^(b), —NO₂,—OR^(a), —NR^(a)R^(b), —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),—S(O)_(m)R^(a), —NR^(a)S(O)₂R^(b), and —SO₂NR^(a)R^(b), or optionallyR^(a) and R^(b) are combined to form a four, five- or six-membered ring,and X¹ is selected from the group consisting of a bond, C₂₋₆alkene,C₂₋₆alkyne, —C(O)—, and —C(O)—(CH₂)₁₋₄—, wherein the aliphatic portionsof X¹ are optionally substituted with one to three members selected fromhalogen, C₁₋₄alkyl, C₁₋₄substituted alkyl and C₁₋₄haloalkyl.

Turning next to R², each R² is a member independently selected from thegroup consisting of halogen, C₁₋₅ alkyl, C₁₋₅substituted alkyl,C₃₋₇cycloalkyl, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —OR^(a),—NR^(a)R^(b), —NR^(a)COR^(b), —SOR^(a)R^(b), —SO₂R^(a) and—SO₂NR^(a)R^(b), and wherein when the subscript q is 2 and R² is alkylor substituted alkyl, the two R² members can optionally cyclize to forma ring.

R³ is a member selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, and C₁₋₄haloalkyl.

Each R⁷ of Formula II is independently selected from the groupconsisting of halo, C₁₋₁₀alkyl, C₁₋₁₀substituted alkyl, C₃₋₇cycloalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, CN, NO₂, —OR^(a), —NR^(a)R^(b), —COR^(a),—CO₂R^(a), —CONR^(a)R^(b), —NR^(a)COR^(b), —NR^(a)CO₂R^(b),—NR^(a)CONR^(a)R^(b), —S(O)_(m)R^(a), —NR^(a)S(O)_(m)R^(b),—SO₂NR^(a)R^(b), a 4- to 7-membered heterocyclo group, aryl and a 5- to10-membered heteroaryl group, wherein each of said heterocyclo groups,said aryl and heteroaryl groups are optionally substituted with from oneto four substituents independently selected from halo, oxo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, CN, NO₂, —OR^(a), —NR^(a)R^(b),—COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —NR^(a)COR^(b), —NR^(a)CO₂R^(b),—NR^(a)CONR^(a)R^(b), —S(O)_(m)R^(a), —NR^(a)SO₂R^(b), and—SO₂NR^(a)R^(b) and wherein the subscript m is an integer of from 0 to2, or optionally R^(a) and R^(b) are combined to form a four, five- orsix-membered ring.

R⁸ is a member independently selected from the group consisting ofhydrogen, C₁₋₄alkyl, and C₁₋₄haloalkyl.

For each of the above groups, each R^(a) and R^(b) is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl,C₁₋₁₀haloalkyl, C₃₋₁₀cycloalkyl, heterocyclyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl, 5- to 6-membered heteroaryl and arylC₁₋₄alkyl; andwherein the aliphatic portions of each of said R^(a) and R^(b) isoptionally substituted with from one to three members selected from thegroup consisting of halo, —OR^(n), —OCOR^(n), —OC(O)N(R^(n))₂, —SR^(n),—S(O)R^(n), —S(O)₂R^(n), —S(O)₂N(R^(n))₂, —NR^(n)S(O)₂R^(n),—C(O)N(R^(n))₂, —C(O)R^(n), —NR^(n)C(O)R^(n), —NR^(n)C(O)N(R^(n))₂,—CO₂R^(n), —NR^(n)CO₂R^(n), —CN, —NO₂, —N(R^(n))₂ and—NR^(n)S(O)₂N(R^(n))₂, wherein each R^(n) is independently hydrogen oran unsubstituted C₁₋₆ alkyl; and wherein the aryl and heteroarylportions are optionally substituted with from one to three membersselected from halogen, —OR^(m), —OC(O)N(R^(m))₂, —SR^(m), —S(O)R^(m),—S(O)₂R^(m), —S(O)₂N(R^(m))₂, —NR^(m)S(O)₂R^(m), —C(O)N(R^(m))₂,—C(O)R^(m), —NR^(m)C(O)R^(m), —NR^(m)C(O)N(R^(m))₂, —CO₂R^(m),—NR^(m)CO₂R^(m), —CN, —NO₂, —N(R^(m))₂ and —NR^(m)S(O)₂N(R^(m))₂,wherein each R^(m) is independently hydrogen or an unsubstituted C₁₋₆alkyl.

The compounds provided herein also include any pharmaceuticallyacceptable salts of the compounds as well as any isotopically labeledisomers thereof. In general, the compounds useful in the methodsdescribed herein are those compound of the formula above, wherein themolecular weight of the compound is less than 1200, more preferably lessthan about 1000, still more preferably less than about 800 and stillmore preferably from about 200 to about 600.

In one embodiment, a preferred R¹ group is selected from the groupconsisting of —X¹—COR^(a), —X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), SO₂R^(a),aryl, heteroaryl, substituted aryl and substituted heteroaryl. When R¹is an aromatic subsituent, R¹ is preferably selected from the groupconsisting of pyridyl, substituted pyridyl, pyrimidinyl, substitutedpyrimidinyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substitutedpyridazinyl, phenyl, substituted phenyl, imidazolyl, triazolyl,substituted triazolyl, substituted imidazolyl, oxazolyl, substitutedoxazolyl, thiazolyl, substituted thiazolyl, oxadiazolyl, substitutedoxadiazolyl, tetrazolyl, and substituted tetrazolyl.

When R¹ is an aromatic subsituent, e.g., aryl or heteroaryl, R¹ can besubstituted with from one to three substitutents selected from the groupconsisting of C₁₋₁₀alkyl, C₁₋₁₀haloalkyl, C₃₋₇cycloalkyl, aryl,heteroaryl, NO₂, —OR^(a), —NR^(a)R^(b), —CO₂R^(a), —CONR^(a)R^(b),—S(O)_(m)R^(a), —NR^(a)S(O)₂R^(b), and —SO₂NR^(a)R^(b).

In one embodiment, a preferred R² is a member independently selectedfrom the group consisting of halo, C₁₋₅alkyl, C₁₋₅haloalkyl, and thesubscript q is an integer of from 0 to 2.

In another preferred embodiment, D is O. In compounds of Formula II,when D is O, a preferred R¹ group is selected from the group consistingof —X¹—COR^(a), —X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), SO₂R^(a), aryl,heteroaryl, substituted aryl and substituted heteroaryl. When R¹ is anaromatic subsituent, R¹ is preferably selected from the group consistingof pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl,pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl,phenyl, substituted phenyl, imidazolyl, triazolyl, substitutedtriazolyl, substituted imidazolyl, oxazolyl, substituted oxazolyl,thiazolyl, substituted thiazolyl, oxadiazolyl, substituted oxadiazolyl,tetrazolyl, and substituted tetrazolyl.

Additionally, when D is O, and R¹ is an aromatic subsituent, e.g., arylor heteroaryl, R¹ can be substituted with from one to threesubstitutents selected from the group consisting of C₁₋₁₀alkyl,C₁₋₁₀haloalkyl, C₃₋₇cycloalkyl, aryl, heteroaryl, NO₂, —OR^(a),—NR^(a)R^(b), —CO₂R^(a), —CONR^(a)R^(b), —S(O)_(m)R^(a),—NR^(a)S(O)₂R^(b), and —SO₂NR^(a)R^(b).

Yet another embodiment of this invention is a compound of Formula IIwherein J, K, T, and U are all C. In this embodiment, a preferred R¹group is selected from the group consisting of —X¹—COR^(a),—X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), SO₂R^(a), aryl, heteroaryl, substitutedaryl and substituted heteroaryl. When R¹ is an aromatic subsituent, R¹is preferably selected from the group consisting of pyridyl, substitutedpyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substitutedpyrazinyl, pyridazinyl, substituted pyridazinyl, phenyl, substitutedphenyl, imidazolyl, triazolyl, substituted triazolyl, substitutedimidazolyl, oxazolyl, substituted oxazolyl, thiazolyl, substitutedthiazolyl, oxadiazolyl, substituted oxadiazolyl, tetrazolyl, andsubstituted tetrazolyl. Further, when J, K, T, and U are all C, and R¹is an aromatic subsituent, e.g., aryl or heteroaryl, R¹ can besubstituted with from one to three substitutents selected from the groupconsisting of C₁₋₁₀alkyl, C₁₋₁₀haloalkyl, C₃₋₇cycloalkyl, aryl,heteroaryl, NO₂, —OR^(a), —NR^(a)R^(b), —CO₂R^(a), —CONR^(a)R^(b),—S(O)_(m)R^(a), —NR^(a)S(O)₂R^(b), and —SO₂NR^(a)R^(b).

One embodiment of this invention comprises compounds of Formula IIwherein the subscript p is an integer of from 1 to 3 and each R⁷ isindependently selected from the group consisting of halo, C₁₋₁₀alkyl,C₁₋₁₀haloalkyl, CN, NO₂, —OR^(a), —NR^(a)R^(b), —COR^(a), —CO₂R^(a),—CONR^(a)R^(b), —NR^(a)COR^(b), —NR^(a)CO₂R^(b), —S(O)_(m)R^(a),—NR^(a)S(O)_(m)R^(b), —SO₂NR^(a)R^(b), a 4- to 7-membered heterocyclogroup, aryl and a 5- to 10-membered heteroaryl group, wherein each ofsaid heterocyclo groups, said aryl and heteroaryl groups are optionallysubstituted with from one to four substituents independently selectedfrom halo, oxo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, CN, NO₂,—OR^(a), —NR^(a)R^(b), —CO₂R^(a), —CONR^(a)R^(b), —NR^(a)COR^(b),—NR^(a)CO₂R^(b), —S(O)_(m)R^(a), —NR^(a)SO₂R^(b), and —SO₂NR^(a)R^(b)and wherein the subscript m is an integer of from 0 to 2.

Yet another aspect of this invention provides compounds of Formula IIwherein J, K, T, and U are all C; a preferred R¹ group is selected fromthe group consisting of —X¹—COR^(a), —X¹—CO₂R^(a), —X¹—CONR^(a)R^(b),SO₂R^(a), aryl, heteroaryl, substituted aryl and substituted heteroaryl.When R¹ is an aromatic subsituent, R¹ is preferably selected from thegroup consisting of pyridyl, substituted pyridyl, pyrimidinyl,substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, pyridazinyl,substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl,triazolyl, substituted triazolyl, substituted imidazolyl, oxazolyl,substituted oxazolyl, thiazolyl, substituted thiazolyl, oxadiazolyl,substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl; and thesubscript p is an integer of from 1 to 3 and each R⁷ is independentlyselected from the group consisting of halo, C₁₋₁₀alkyl, C₁₋₁₀haloalkyl,CN, NO₂, —OR^(a), —NR^(a)R^(b), —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),—NR^(a)COR^(b), —NR^(a)CO₂R^(b), —S(O)_(m)R^(a), —NR^(a)S(O)_(m)R^(b),—SO₂NR^(a)R^(b), a 4- to 7-membered heterocyclo group, aryl and a 5- to10-membered heteroaryl group, wherein each of said heterocyclo groups,said aryl and heteroaryl groups are optionally substituted with from oneto four substituents independently selected from halo, oxo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, CN, NO₂, —OR^(a), —NR^(a)R^(b),—CO₂R^(a), —CONR^(a)R^(b), —NR^(a)COR^(b), —NR^(a)CO₂R^(b),—S(O)_(m)R^(a), —NR^(a)SO₂R^(b), and —SO₂NR^(a)R^(b) and wherein thesubscript m is an integer of from 0 to 2. Optionally, R¹ is substitutedwith from one to three substitutents selected from the group consistingof C₁₋₁₀alkyl, C₁₋₁₀haloalkyl, C₃₋₇cycloalkyl, aryl, heteroaryl, NO₂,—OR^(a), —NR^(a)R^(b), —CO₂R^(a), —CONR^(a)R^(b), —S(O)_(m)R^(a),—NR^(a)S(O)₂R^(b), and —SO₂NR^(a)R^(b).

A further embodiment of the compounds of the invention are compounds ofFormula II, wherein at least one of J, K, T, and U is N. In thisembodiment, D is O, S, or NR⁸.

A preferred embodiment of Formula II provides compounds wherein at leastone of J, K, T, and U is N and D is O.

In compounds of Formula II when at least one of J, K, T, and U is N andD is O, a preferred R¹ group is selected from the group consisting of—X¹—COR^(a), —X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), SO₂R^(a), aryl,heteroaryl, substituted aryl and substituted heteroaryl. When R¹ is anaromatic subsituent, R¹ is preferably selected from the group consistingof pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl,pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl,phenyl, substituted phenyl, imidazolyl, substituted imidazolyl,triazolyl, substituted triazolyl, oxazolyl, substituted oxazolyl,thiazolyl, substituted thiazolyl, oxadiazolyl, substituted oxadiazolyl,tetrazolyl, and substituted tetrazolyl; and the subscript p is aninteger of from 1 to 3 and each R⁷ is independently selected from thegroup consisting of halo, C₁₋₁₀alkyl, C₁₋₁₀haloalkyl, CN, NO₂, —OR^(a),—NR^(a)R^(b), —COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —NR^(a)COR^(b),—NR^(a)CO₂R^(b), —S(O)_(m)R^(a), —NR^(a)S(O)_(m)R^(b), —SO₂NR^(a)R^(b),a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-memberedheteroaryl group, wherein each of said heterocyclo groups, said aryl andheteroaryl groups are optionally substituted with from one to foursubstituents independently selected from halo, oxo, C₁₋₄ alkyl,C₁₋₄haloalkyl, C₃₋₇ cycloalkyl, CN, NO₂, —OR^(a), —NR^(a)R^(b),—CO₂R^(a), —CONR^(a)R^(b), —NR^(a)COR^(b), —NR^(a)CO₂R^(b),—S(O)_(m)R^(a), —NR^(a)SO₂R^(b), and —SO₂NR^(a)R^(b) and wherein thesubscript m is an integer of from 0 to 2. Optionally, R¹ is substitutedwith from one to three substitutents selected from the group consistingof C₁₋₁₀alkyl, C₁₋₁₀haloalkyl, C₃₋₇cycloalkyl, aryl, heteroaryl, NO₂,—OR^(a), —NR^(a)R^(b), —CO₂R^(a), —CONR^(a)R^(b), —S(O)_(m)R^(a),—NR^(a)S(O)₂R^(b), and —SO₂NR^(a)R^(b).

One preferred embodiment provides compounds of Formula II wherein whenat least one of J, K, T, and U is N and D is O, and R¹ is as describedin the above paragraph, the subscript p is an integer of from 1 to 3 andeach R⁷ is independently selected from the group consisting of halo,C₁₋₁₀alkyl, C₁₋₁₀haloalkyl, CN, NO₂, —OR^(a), —NR^(a)R^(b), —COR^(a),—CO₂R^(a), —CONR^(a)R^(b), —NR^(a)COR^(b), —NR^(a)CO₂R^(b),—S(O)_(m)R^(a), —NR^(a)S(O)_(m)R^(b), —SO₂NR^(a)R^(b), a 4- to7-membered heterocyclo group, aryl and a 5- to 10-membered heteroarylgroup, wherein each of said heterocyclo groups, said aryl and heteroarylgroups are optionally substituted with from one to four substituentsindependently selected from halo, oxo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇cycloalkyl, CN, NO₂, —OR^(a), —NR^(a)R^(b), —CO₂R^(a), —CONR^(a)R^(b),—NR^(a)COR^(b), —NR^(a)CO₂R^(b), —S(O)_(m)R^(a), —NR^(a)SO₂R^(b), and—SO₂NR^(a)R^(b) and wherein the subscript m is an integer of from 0 to2.

Yet another preferred compound of Formula II provides compounds whereinJ, T, and U are all C, and D is O, S, or NR⁸.

An even more preferred compound of Formula II provides compounds whereinJ, T, and U are all C, and D is O.

For compounds of Formula II when J, T, and U are all C, and D is O, theR⁷ group is a member independently selected from the group consisting ofhalo, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, CN, NO₂, —OR^(a), —NR^(a)R^(b),—COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —NR^(a)COR^(b), —NR^(a)CO₂R^(b),—S(O)_(m)R^(a), —NR^(a)S(O)_(m)R^(b), —SO₂NR^(a)R^(b), a 4- to5-membered heterocyclo group, and a 5- to 6-membered heteroaryl groupand wherein the subscript m is an integer of from 0 to 2. Preferred R⁷groups are independently selected from the group consisting of halo,C₁₋₅alkyl, C₁₋₅haloalkyl, —SOR^(a), —SO₂R^(a), and 5-membered heteroarylgroup. Even more preferred R⁷ groups are independently selected from thegroup consisting of fluoro, chloro, methyl, ethyl, —CF₃, —SO₂CH₃,imidazolyl, triazolyl, and tetrazolyl and wherein the subscript p isinteger of from 1 to 2.

In Formula II, when J, T, and U are all C, and D is O, preferredcompounds are compounds wherein the R⁷ group is a member independentlyselected from the group consisting of halo, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, CN, NO₂, —OR^(a), —NR^(a)R^(b), —COR^(a), —CO₂R^(a),—CONR^(a)R^(b), —NR^(a)COR^(b), —NR^(a)CO₂R^(b), —S(O)_(m)R^(a),—NR^(a)S(O)_(m)R^(b), —SO₂NR^(a)R^(b), a 4- to 5-membered heterocyclogroup, and a 5- to 6-membered heteroaryl group and wherein the subscriptm is an integer of from 0 to 2, and each R² is a member independentlyselected from the group consisting of halo, C₁₋₅alkyl, C₁₋₅haloalkyl,and the subscript q is an integer of from 0 to 2. Preferred R⁷ groupsare independently selected from the group consisting of halo, C₁₋₅alkyl,C₁₋₅haloalkyl, —SOR^(a), —SO₂R^(a), and 5-membered heteroaryl group.Even more preferred R⁷ groups are independently selected from the groupconsisting of fluoro, chloro, methyl, ethyl, —CF₃, —SO₂C₁₋₃alkyl,imidazolyl, triazolyl, and tetrazolyl and wherein the subscript p isinteger of from 1 to 2.

Another embodiment of the invention provides compounds of Formula IIwherein when J, T, and U are all C, and D is O, the R⁷ group is a memberas described above, and R¹ is selected from the group consisting of—X¹—COR^(a), —X¹CO₂R^(a), —X¹—CONR^(a)R^(b), SO₂R^(a), aryl, heteroaryl,substituted aryl and substituted heteroaryl. A Preferred R¹ group isselected from the group consisting of is aryl, heteroaryl, substitutedaryl and substituted heteroaryl. Even more preferred are compoundswherein R¹ is selected from the group consisting of pyridyl, substitutedpyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substitutedpyrazinyl, pyridazinyl, substituted pyridazinyl, phenyl, substitutedphenyl, imidazolyl, triazolyl, substituted triazolyl, substitutedimidazolyl, oxazolyl, substituted oxazolyl, thiazolyl, substitutedthiazolyl, oxadiazolyl, substituted oxadiazolyl, tetrazolyl, andsubstituted tetrazolyl. Yet even more preferred are compounds wherein R¹is selected from the group consisting of pyrimidinyl, substitutedpyrimidinyl, oxadiazolyl, substituted oxadiazolyl, and —X¹—CO₂R^(a) andwherein X¹ is a bond.

Additional preferred compounds of the invention are compounds wherein,J, T, and U are all C; and D is O, X is S, Y is C, Z is N; R¹ isselected from the group consisting of pyrimidinyl, substitutedpyrimidinyl, pyridyl, and substituted pyridyl, each R⁷ is independentlyselected from the group consisting of fluoro and tetrazolyl.

In one aspect, this invention provides method of treating a disease orcondition selected from the group consisting of Type I diabetes, Type IIdiabetes and metabolic syndrome. The method comprises administering to asubject in need of such treatment an effective amount of a compound ofFormula I or Formula II.

Another aspect of this invention provides methods of stimulating insulinproduction in a mammal comprising administering an effective amount of acompound of Formula I or Formula II to the mammal. In one aspect thebeta cell of the pancreas is stimulated to produce insulin.

Yet another aspect of this invention provides methods of stimulatingglucose dependent insulin secretion or production in a mammal comprisingadministering an effective amount of a compound of Formula I or FormulaII to the mammal. In one aspect the beta cell of the pancreas isstimulated to secret insulin.

A further aspect of this invention is a method of lowering blood glucosein a mammal. The method comprises administering an effective amount of acompound of Formula I or Formula II to the mammal. The method furthercomprises steps to measure blood glucose levels before and afteradministration of a compound of the invention. Blood glucose levels areeasily measured by numerous commercially available glucose monitoringdevices that measure blood glucose from samples of blood or urine. Bloodglucose can also be measured by commercially available glucometers thatdo not require blood or urine samples. Biological Example 5 providesmethods of measuring glucose levels.

In another embodiment, this invention provides a method of lowereingblood triglycerides in a mammal. The method comprises administering aneffective amount of a compound of Formula I or Formula II to the mammal.The method further comprises steps to measure blood triglycerides levelsbefore and after administration of a compound of the invention. Bloodtriglyceride levels are easily measured by numerous commerciallyavailable devices that measure blood triglyceride levels from samples ofblood. Biological Example 6 provides methods measuring triglyceridelevels.

Preparation of Compounds of the Invention

The compounds of the present invention can be prepared in a number ofways familiar to one skilled in the art of organic synthesis. Thesynthetic route of compounds in the present invention is not limited tothe methods outlined below or as provided in the Examples. Individualcompounds may require manipulation of the conditions in order toaccommodate various functional groups and may require appropriate use ofprotecting groups. Purification, if necessary, can be accomplished on asilica gel column eluted with the appropriate organic solvent system.Also, reverse phase HPLC or recrystallization may be employed.

One aspect of the present invention provides methods of raisingintracellular levels of cyclic AMP (cAMP) in a cell expressing GPR119.The method comprises exposing a cell that expresses GPR119 to a compoundas described herein. Cyclic AMP levels are determined by the methodsdisclosed herein. Preferred cells that express GPR119 are pancreaticcells, islet cells, beta cells, intestinal endocrine cells, and L cellsor K cells.

Selected thiazole compounds of Formula I can be prepared using methodsgenerally outlined in Scheme 1.

According to Scheme 1, a thioamide can be condensed with a chloromethylketone to form a suitable thiazole intermediate. Manipulations of the R₁and R₂ groups can be accomplished as provided in the Examples below.

Similarly, oxadiazole compounds of Formula I can be prepared asgenerally shown in Scheme 2.

Here, treatment of a suitable nitrile with NH₂OH.HCl in the presence ofK₂CO₃ (step 1) provides the N-hydroxy amidine, which can be converted toan oxadiazole compounds using, for example, R₂COOH,isobutylchloroformate, and triethylamine. As above, further manipulationof R₁ and R₂ can be carried out as provided in the Examples below.

Compositions and Methods of Treatment

In accordance with the present invention, a therapeutically effectiveamount of a compound of Formula I can be used for the preparation of apharmaceutical composition useful for treating Type II diabetes and/orlowering the plasma level of glucose. In addition, a therapeuticallyeffective amount of a compound of Formula I can be used for thepreparation of a pharmaceutical composition useful for treating otherindications that include diabetes as a component, such metabolicsyndrome, as well as indications that can be improved as a result ofincreased insulin production (such as the early stages of Type Idiabetes).

The compositions of the invention can include compounds of Formula I andFormula II, pharmaceutically acceptable salts thereof, or a hydrolysableprecursor thereof. In general, the compound is mixed with suitablecarriers or excipient(s) in a therapeutically effective amount. By a“therapeutically effective dose”, “therapeutically effective amount”,or, interchangeably, “pharmacologically acceptable dose” or“pharmacologically acceptable amount”, it is meant that a sufficientamount of the compound of the present invention and a pharmaceuticallyacceptable carrier, will be present in order to achieve a desiredresult, e.g., alleviating a symptom or complication of Type II diabetes.

The compounds of Formula I and Formula II that are used in the methodsof the present invention can be incorporated into a variety offormulations for therapeutic administration. More particularly, thecompounds of Formula I and Formula II can be formulated intopharmaceutical compositions by combination with appropriate,pharmaceutically acceptable carriers or diluents, and can be formulatedinto preparations in solid, semi-solid, liquid or gaseous forms, such astablets, capsules, pills, powders, granules, dragees, gels, slurries,ointments, solutions, suppositories, injections, inhalants and aerosols.As such, administration of the compounds can be achieved in variousways, including oral, buccal, rectal, parenteral, intraperitoneal,intradermal, transdermal, and/or intratracheal administration. Moreover,the compound can be administered in a local rather than systemic manner,in a depot or sustained release formulation. In addition, the compoundscan be administered in a liposome.

The compounds of Formula I and Formula II can be formulated with commonexcipients, diluents or carriers, and compressed into tablets, orformulated as elixirs or solutions for convenient oral administration,or administered by the intramuscular or intravenous routes. Thecompounds can be administered transdermally, and can be formulated assustained release dosage forms and the like. Compounds of Formula I orFormula II can be administered alone, in combination with each other, orthey can be used in combination with other known compounds (seeCombination Therapy below).

Suitable formulations for use in the present invention are found inRemington's Pharmaceutical Sciences (Mack Publishing Company (1985)Philadelphia, Pa., 17th ed.), which is incorporated herein by reference.Moreover, for a brief review of methods for drug delivery, see, Langer,Science (1990) 249:1527-1533, which is incorporated herein by reference.The pharmaceutical compositions described herein can be manufactured ina manner that is known to those of skill in the art, i.e., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilizing processes. Thefollowing methods and excipients are merely exemplary and are in no waylimiting.

For injection, the compounds can be formulated into preparations bydissolving, suspending or emulsifying them in an aqueous or nonaqueoussolvent, such as vegetable or other similar oils, synthetic aliphaticacid glycerides, esters of higher aliphatic acids or propylene glycol;and if desired, with conventional additives such as solubilizers,isotonic agents, suspending agents, emulsifying agents, stabilizers andpreservatives. Preferably, the compounds of the present invention can beformulated in aqueous solutions, preferably in physiologicallycompatible buffers such as Hanks's solution, Ringer's solution, orphysiological saline buffer. For transmucosal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art.

For oral administration, the compounds of Formula I or Formula II can beformulated readily by combining with pharmaceutically acceptablecarriers that are well known in the art. Such carriers enable thecompounds to be formulated as tablets, pills, dragees, capsules,emulsions, lipophilic and hydrophilic suspensions, liquids, gels,syrups, slurries, suspensions and the like, for oral ingestion by apatient to be treated. Pharmaceutical preparations for oral use can beobtained by mixing the compounds with a solid excipient, optionallygrinding a resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain tablets ordragee cores. Suitable excipients are, in particular, fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone. If desired, disintegrating agents can be added,such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid ora salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds can be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers can be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions can take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas, or from propellant-free, dry-powder inhalers. In thecase of a pressurized aerosol the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, e.g., gelatin for use in an inhaler or insufflator can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

The compounds can be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection can be presented in unit dosage form, e.g., in ampules orin multidose containers, with an added preservative. The compositionscan take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and can contain formulator agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds can be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions can contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension can also contain suitablestabilizers or agents that increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.Alternatively, the active ingredient can be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The compounds can also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, carbowaxes, polyethylene glycolsor other glycerides, all of which melt at body temperature, yet aresolidified at room temperature.

In addition to the formulations described previously, the compounds canalso be formulated as a depot preparation. Such long acting formulationscan be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds can be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds can be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. In apresently preferred embodiment, long-circulating, i.e., stealthliposomes can be employed. Such liposomes are generally described inWoodle, et al., U.S. Pat. No. 5,013,556. The compounds of the presentinvention can also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; and 4,008,719.

Certain organic solvents such as dimethylsulfoxide (“DMSO”) also can beemployed, although usually at the cost of greater toxicity.Additionally, the compounds can be delivered using a sustained-releasesystem, such as semipermeable matrices of solid hydrophobic polymerscontaining the therapeutic agent. Various types of sustained-releasematerials have been established and are well known by those skilled inthe art. Sustained-release capsules can, depending on their chemicalnature, release the compounds for a few hours up to over 100 days.

The pharmaceutical compositions also can comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in atherapeutically effective amount. The amount of composition administeredwill, of course, be dependent on the subject being treated, on thesubject's weight, the severity of the affliction, the manner ofadministration and the judgment of the prescribing physician.Determination of an effective amount is well within the capability ofthose skilled in the art, especially in light of the detailed disclosureprovided herein.

For any compound used in the method of the present invention, atherapeutically effective dose can be estimated initially from cellculture assays, animal models, or microdosing of human subjects.

Moreover, toxicity and therapeutic efficacy of the compounds describedherein can be determined by standard pharmaceutical procedures in cellcultures or experimental animals, e.g., by determining the LD₅₀, (thedose lethal to 50% of the population) and the ED₅₀ (the dosetherapeutically effective in 50% of the population). The dose ratiobetween toxic and therapeutic effect is the therapeutic index and can beexpressed as the ratio between LD₅₀ and ED₅₀. Compounds that exhibithigh therapeutic indices are preferred. The data obtained from thesecell culture assays and animal studies can be used in formulating adosage range that is not toxic for use in human. The dosage of suchcompounds lies preferably within a range of circulating concentrationsthat include the ED₅₀ with little or no toxicity. The dosage can varywithin this range depending upon the dosage form employed and the routeof administration utilized. The exact formulation, route ofadministration and dosage can be chosen by the individual physician inview of the patient's condition. (See, e.g., Fingl, et al., 1975 In: ThePharmacological Basis of Therapeutics, Ch. 1).

The amount of active compound that can be combined with a carriermaterial to produce a single dosage form will vary depending upon thedisease treated, the mammalian species, and the particular mode ofadministration. However, as a general guide, suitable unit doses for thecompounds of the present invention can, for example, preferably containbetween 0.1 mg to about 1000 mg of the active compound. A preferred unitdose is between 1 mg to about 100 mg. A more preferred unit dose isbetween 1 mg to about 20 mg. Such unit doses can be administered morethan once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably1 or 2 times per day, so that the total dosage for a 70 kg adult is inthe range of 0.001 to about 15 mg per kg weight of subject peradministration. A preferred dosage is 0.01 to about 1.5 mg per kg weightof subject per administration, and such therapy can extend for a numberof weeks or months, and in some cases, years. It will be understood,however, that the specific dose level for any particular patient willdepend on a variety of factors including the activity of the specificcompound employed; the age, body weight, general health, sex and diet ofthe individual being treated; the time and route of administration; therate of excretion; other drugs that have previously been administered;and the severity of the particular disease undergoing therapy, as iswell understood by those of skill in the area.

A typical dosage can be one 1 mg to about 20 mg tablet taken once a day,or, multiple times per day, or one time-release capsule or tablet takenonce a day and containing a proportionally higher content of activeingredient. The time-release effect can be obtained by capsule materialsthat dissolve at different pH values, by capsules that release slowly byosmotic pressure, or by any other known means of controlled release.

It can be necessary to use dosages outside these ranges in some cases aswill be apparent to those skilled in the art. Further, it is noted thatthe clinician or treating physician will know how and when to interrupt,adjust, or terminate therapy in conjunction with individual patientresponse.

Combination Therapy

As noted above, the compounds of the present invention will, in someinstances, be used in combination with other therapeutic agents to bringabout a desired effect. Selection of additional agents will, in largepart, depend on the desired target therapy (see, e.g., Turner N, et al.,Prog. Drug Res. (1998) 51:33-94; Haffner S, Diabetes Care (1998)21:160-178; and DeFronzo R, et al. (eds.), Diabetes Reviews (1997) Vol.5 No. 4). A number of studies have investigated the benefits ofcombination therapies with oral agents (see, e.g., Mahler R, J. Clin.Endocrinol. Metab. (1999) 84:1165-71; United Kingdom ProspectiveDiabetes Study Group: UKPDS 28, Diabetes Care (1998) 21:87-92; Bardin CW (ed.), Current Therapy in Endocrinology and Metabolism, 6th Edition(Mosby-Year Book, Inc., St. Louis, Mo. 1997); Chiasson J, et al., Ann.Intern. Med. (1994) 121:928-935; Coniff R, et al., Clin. Ther. (1997)19:16-26; Coniff R, et al., Am. J. Med. (1995) 98:443-451; and IwamotoY, et al., Diabet. Med. (1996) 13 365-370; Kwiterovich P, Am. J. Cardiol(1998) 82(12A):3U-17U). These studies indicate that diabetes modulationcan be further improved by the addition of a second agent to thetherapeutic regimen. Combination therapy includes administration of asingle pharmaceutical dosage formulation that contains a compound havingthe general structure of Formula I or Formula II and one or moreadditional active agents, as well as administration of a compound ofFormula I or Formula II and each active agent in its own separatepharmaceutical dosage formulation. For example, a compound of Formula Ior Formula II and a DPP-IV inhibitor can be administered to the humansubject together in a single oral dosage composition, such as a tabletor capsule, or each agent can be administered in separate oral dosageformulations. Where separate dosage formulations are used, a compound ofFormula I or Formula II and one or more additional active agents can beadministered at essentially the same time (i.e., concurrently), or atseparately staggered times (i.e., sequentially). Combination therapy isunderstood to include all these regimens.

An example of combination therapy can be seen in modulating (preventingthe onset of the symptoms or complications associated with) diabetes (ortreating, preventing or reducing the risk of developing, diabetes andits related symptoms, complications, and disorders), wherein thecompounds of Formula I or Formula II can be effectively used incombination with, for example, biguanides (such as metformin);thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, androsiglitazone); dipeptidyl-peptidase-4 (“DPP-IV”) inhibitors (such asvildagliptin and sitagliptin); glucagonlike peptide-1 (“GLP-1”) receptoragonists (such as exanatide) (or GLP-1 mimetics); PPAR gamma agonists orpartial agonists; dual PPAR alpha, PPAR gamma agonists or partialagonists; dual PPAR delta, PPAR gamma agonists or partial agonists; panPPAR agonists or partial agonists; dehydroepiandrosterone (also referredto as DHEA or its conjugated sulphate ester, DHEA-SO₄);antiglucocorticoids; TNFα inhibitors; α-glucosidase inhibitors (such asacarbose, miglitol, and voglibose); sulfonylureas (such aschlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide,gliclazide, glynase, glimepiride, and glipizide); pramlintide (asynthetic analog of the human hormone amylin); other insulinsecretogogues (such as repaglinide, gliquidone, and nateglinide);insulin (or insulin mimetics); glucagon receptor antagonists; gastricinhibitory peptide (“GIP”); or GIP mimetics; as well as the activeagents discussed below for treating obesity, hyperlipidemia,atherosclerosis and/or metabolic syndrome.

Another example of combination therapy can be seen in treating obesityor obesity-related disorders, wherein the compounds of Formula I orFormula II can be effectively used in combination with, for example,phenylpropanolamine, phenteramine; diethylpropion; mazindol;fenfluramine; dexfenfluramine; phentiramine, β-3 adrenoceptor agonistagents; sibutramine; gastrointestinal lipase inhibitors (such asorlistat); and leptins. Other agents used in treating obesity orobesity-related disorders wherein the compounds of Formula I or FormulaII can be effectively used in combination with, for example,cannabinoid-1 (“CB-1”) receptor antagonists (such as rimonabant); PPARdelta agonists or partial agonists; dual PPAR alpha, PPAR delta agonistsor partial agonists; dual PPAR delta, PPAR gamma agonists or partialagonists; pan PPAR agonists or partial agonists; neuropeptide Y;enterostatin; cholecytokinin; bombesin; amylin; histamine H₃ receptors;dopamine D₂ receptors; melanocyte stimulating hormone; corticotrophinreleasing factor; galanin; and gamma amino butyric acid (GABA).

Still another example of combination therapy can be seen in modulatinghyperlipidemia (treating hyperlipidemia and its related complications),wherein the compounds of Formula I or Formula II can be effectively usedin combination with, for example, statins (such as atorvastatin,fluvastatin, lovastatin, pravastatin, and simvastatin), CETP inhibitors(such as torcetrapib); a cholesterol absorption inhibitor (such asezetimibe); PPAR alpha agonists or partial agonists; PPAR delta agonistsor partial agonists; dual PPAR alpha, PPAR delta agonists or partialagonists; dual PPAR alpha, PPAR gamma agonists or partial agonists; dualPPAR delta, PPAR gamma agonists or partial agonists; pan PPAR agonistsor partial agonists; fenofibric acid derivatives (such as gemfibrozil,clofibrate, fenofibrate, and bezafibrate); bile acid-binding resins(such as colestipol or cholestyramine); nicotinic acid; probucol;betacarotene; vitamin E; or vitamin C.

A further example of combination therapy can be seen in modulatingatherosclerosis, wherein a compound of Formula I or Formula II isadministered in combination with one or more of the following activeagents: an antihyperlipidemic agent; a plasma HDL-raising agent; anantihypercholesterolemic agent, such as a cholesterol biosynthesisinhibitor, e.g., an hydroxymethylglutaryl (HMG) CoA reductase inhibitor(also referred to as statins, such as lovastatin, simvastatin,pravastatin, fluvastatin, and atorvastatin); an HMG-CoA synthaseinhibitor; a squalene epoxidase inhibitor; or a squalene synthetaseinhibitor (also known as squalene synthase inhibitor); an acyl-coenzymeA cholesterol acyltransferase (ACAT) inhibitor, such as melinamide;probucol; nicotinic acid and the salts thereof and niacinamide; acholesterol absorption inhibitor, such as β-sitosterol; a bile acidsequestrant anion exchange resin, such as cholestyramine, colestipol ordialkylaminoalkyl derivatives of a cross-linked dextran; an LDL receptorinducer; fibrates, such as clofibrate, bezafibrate, fenofibrate, andgemfibrizol; vitamin B₆ (also known as pyridoxine) and thepharmaceutically acceptable salts thereof, such as the HCl salt; vitaminB₁₂ (also known as cyanocobalamin); vitamin B₃ (also known as nicotinicacid and niacinamide); anti-oxidant vitamins, such as vitamin C and Eand beta carotene; a beta-blocker; an angiotensin II antagonist; anangiotensin converting enzyme inhibitor; PPAR alpha agonists or partialagonists; PPAR delta agonists or partial agonists; PPAR gamma agonistsor partial agonists; dual PPAR alpha, PPAR delta agonists or partialagonists; dual PPAR alpha, PPAR gamma agonists or partial agonists; dualPPAR delta, PPAR gamma agonists or partial agonists; pan PPAR agonistsor partial agonists; and a platelet aggregation inhibitor, such asfibrinogen receptor antagonists (i.e., glycoprotein IIb/IIIa fibrinogenreceptor antagonists) and aspirin. As noted above, the compounds ofFormula I or Formula II can be administered in combination with morethan one additional active agent, for example, a combination of acompound of Formula I or Formula II with an HMG-CoA reductase inhibitor(e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, andsimvastatin) and aspirin, or a compound of Formula I or Formula II withan HMG-CoA reductase inhibitor and a β blocker.

Additionally, an effective amount of a compound of Formula I or FormulaII and a therapeutically effective amount of one or more active agentsselected from the group consisting of: an antihyperlipidemic agent; aplasma HDL-raising agent; an antihypercholesterolemic agent, such as acholesterol biosynthesis inhibitor, for example, an HMG-CoA reductaseinhibitor; an HMG-CoA synthase inhibitor; a squalene epoxidaseinhibitor, or a squalene synthetase inhibitor (also known as squalenesynthase inhibitor); an acyl-coenzyme A cholesterol acyltransferaseinhibitor; probucol; nicotinic acid and the salts thereof; CETPinhibitors such as torcetrapib; a cholesterol absorption inhibitor suchas ezetimibe; PPAR alpha agonists or partial agonists; PPAR deltaagonists or partial agonists; dual PPAR alpha, PPAR delta agonists orpartial agonists; dual PPAR alpha, PPAR gamma agonists or partialagonists; dual PPAR delta, PPAR gamma agonists or partial agonists; panPPAR agonists or partial agonists; niacinamide; a cholesterol absorptioninhibitor; a bile acid sequestrant anion exchange resin; a LDL receptorinducer; clofibrate, fenofibrate, and gemfibrozil; vitamin B₆ and thepharmaceutically acceptable salts thereof; vitamin B₁₂; an anti-oxidantvitamin; a β-blocker; an angiotensin II antagonist; an angiotensinconverting enzyme inhibitor; a platelet aggregation inhibitor; afibrinogen receptor antagonist; aspirin; phentiramines, β-3 adrenergicreceptor agonists; sulfonylureas, biguanides, α-glucosidase inhibitors,other insulin secretogogues, and insulin can be used together for thepreparation of a pharmaceutical composition useful for theabove-described treatments.

An additional example of combination therapy can be seen in modulatingmetabolic syndrome (or treating metabolic syndrome and its relatedsymptoms, complications and disorders), wherein the compounds of FormulaI or Formula II can be effectively used in combination with, forexample, the active agents discussed above for modulating or treatingdiabetes, obesity, hyperlipidemia, atherosclerosis, and/or theirrespective related symptoms, complications and disorders.

In a further embodiment, a compound of the present invention can beadministered in combination with halofenic acid, an ester of halofenicacid, or another prodrug of halofenic acid, preferably with(−)-(4-chlorophenyl)-(3-trifluoromethylphenoxy)-acetic acid2-acetylaminoethyl ester (metaglidasen).

Methods of Diagnosis and/or Imaging

Compounds of the present invention are also useful in methods ofdiagnosis and/or imaging. Many direct methods are available to evaluatean agent's biodistribution in the body such as magnetic resonanceimaging (“MRI”), positron emission tomography (“PET”), and single photonemission computed tomography (“SPECT”). Each of these methods can detectthe distribution of a compound within the body if that compound containsan atom with the appropriate nuclear properties. MRI detectsparamagnetic nuclei; PET and SPECT detect the emission of particles fromthe decay of radionuclei.

Most therapeutic agents are not able to be detected by these techniqueswithout modification. Thus, for PET it is necessary to incorporate anappropriate positron-emitting radionuclide. There are relatively fewpositron-emitting isotopes that are suitable for labeling a therapeuticagent. The carbon isotope, ¹¹C, has been used for PET, but has a shorthalf-life of 20.5 minutes. Accordingly, the facilities for synthesis anduse are typically near to a cyclotron where the precursor ¹¹C startingmaterial is generated. Other isotopes have even shorter half-lives. ¹³Nhas a half-life of 10 minutes and ¹⁵O has an even shorter half-life of 2minutes. The emissions of both are more energetic, however, than thoseof ¹¹C and PET studies have been carried out with these isotopes (see,Clinical Positron Emission Tomography, Mosby Year Book, 1992, KF Hubner,et al., Chapter 2). Another useful isotope, ¹⁸F, has a half-life of 110minutes. This allows sufficient time for incorporation into aradiolabeled tracer, for purification and for administration into ahuman or animal subject. ¹⁸F labeled compounds have been used in studiesof glucose metabolism and localization of glucose uptake associated withbrain activity. For example, ¹⁸F-L-fluorodopa and other dopaminereceptor analogs have also been used in mapping dopamine receptordistribution.

SPECT imaging employs isotope tracers that emit high energy photons(γ-emitters). The range of useful isotopes is greater than for PET, butSPECT provides lower three-dimensional resolution. Nevertheless, SPECTis widely used to obtain clinically significant information about analogbinding, localization and clearance rates. A useful isotope for SPECTimaging is ¹²³I, a γ-emitter with a 13.3 hour half life. Compoundslabeled with ¹²³I can be shipped up to about 1000 miles from themanufacturing site, or the isotope itself can be transported for on-sitesynthesis. Eighty-five percent of the isotope's emissions are 159 KeVphotons, which are readily measured by SPECT instrumentation currentlyin use. Other halogen isotopes can serve for PET or SPECT imaging, orfor conventional tracer labeling. These include ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and⁸²Br as having usable half-lives and emission characteristics. Ingeneral, the chemical means exist to substitute any halogen moiety forthe described isotopes. Therefore, the biochemical or physiologicalactivities of any halogenated homolog of the described compounds are nowavailable for use by those skilled in the art, including stable isotopehalogen homologs.

In the context of the present invention, methods are provided fordiagnosing a disease or condition selected from Type I diabetes and TypeII diabetes, the method comprising

(a) administering to a subject having, or at risk for, such a disease orcondition an imaging amount of a compound of the invention, wherein thecompound is isotopically labeled; and(b) imaging the subject to determine the number, mass or volume ofpancreatic beta cells or islet endocrine cells; or to assess thefunction of pancreatic beta cells or islet endocrine cells.

Preferably, the compound is labeled with ¹¹C or ¹⁴C. In other preferredembodiments, the imaging is conducted via PET or SPECT.

Kits

In addition, the present invention provides for kits with unit doses ofthe compounds of Formula I or Formula II, either in oral or injectabledoses. In addition to the containers containing the unit doses will bean informational package insert describing the use and attendantbenefits of the drugs in treating Type II diabetes, obesity,hyperlipidemia, atheroschlerosis and metabolic syndrome, and/or theirrespective related symptoms, complications and disorders. Preferredcompounds and unit doses are those described herein above.

For the compositions, methods and kits provided above, one of skill inthe art will understand that preferred compounds for use in each arethose compounds that are noted as preferred above. Still furtherpreferred compounds for the compositions, methods and kits are thosecompounds provided in the non-limiting Examples below.

EXAMPLES Experimental Section

General Methods:

All operations involving moisture and/or oxygen sensitive materials wereconducted under an atmosphere of dry nitrogen in pre-dried glassware.Unless noted otherwise, materials were obtained from commerciallyavailable sources and used without further purification.

Flash chromatography was performed on E. Merck silica gel 60 (240-400mesh) according to the protocol of Still, Kahn, and Mitra (J. Org. Chem.(1978) 43, 2923). Thin layer chromatography was performed usingprecoated plates purchased from E. Merck (silica gel 60 PF₂₅₄, 0.25 mm)and spots were visualized with ultraviolet light followed by anappropriate staining reagent.

Nuclear magnetic resonance (“NMR”) spectra were recorded on a VarianInova-400 resonance spectrometer. ¹H NMR chemical shifts are given inparts per million (δ) downfield from tetramethylsilane (“TMS”) using TMSor the residual solvent signal (CHCl₃=δ 7.24, DMSO=δ 2.50) as internalstandard. ¹H NMR information is tabulated in the following format:number of protons, multiplicity (s, singlet; d, doublet; t, triplet; q,quartet; m, multiplet), coupling contant(s) (J) in Hertz, and, inselected cases, position assignment. The prefix app is occasionallyapplied in cases where the true signal multiplicity was unresolved andbr indicates the signal in question was broadened.

Preparation of Intermediate 1:4-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butylester

To a solution of 4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butylester (4.9 g, 20 mmol) in acetone (80 mL) was added 1,3-dichloroacetone(3.3 g, 26 mmol), MgSO₄ (3.6 g, 30 mmol) and MgCO₃ (1.68 g, 20 mmol).The mixture was heated under reflux overnight, cooled and filteredthrough celite. The solvent was removed in vacuo and the residue wasredissolved with EtOAc (150 mL). The resulting solution was washedsuccessively with 5% NaHSO₃, saturated NaHCO₃, and brine. After drying(Na₂SO₄), the solvent was removed to afford the desired product. ¹H NMR(CDCl₃): δ 7.20 (1H, s), 4.67 (2H, s), 4.20 (2H, br), 3.16 (1H, m), 2.87(2H, m), 2.09 (2H, m), 1.72 (2H, m), 1.47 (9H, s).

Preparation of Intermediate 2:2-[4-(4-Chloromethyl-thiazol-2-yl)-piperidin-1-yl]-5-ethyl-pyrimidine

Intermediate 2 was prepared in a manner analogous to Intermediate 1above.

¹H NMR (DMSO-d₆): δ 8.45 (2H, d), 7.62 (1H, s), 4.79 (2H, s), 4.61 (2H,m), 3.41 (1H, m), 3.24 (2H, m), 2.52 (2H, q), 2.15 (2H, m), 1.66 (2H,m), 1.17 (3H, m).

Preparation of Intermediate 3:4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine

A solution of4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (615 mg, 1.36 mmol) in methanol (10 mL) wastreated with 10 mL of 4N HCl in dioxane. The resulting solution wasstirred at room temperature for 30 minutes. Then all the solvents wereremoved in vacuo to afford the desired product as a HCl salt.

Preparation of Intermediate 4:4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

Intermediate 4 was prepared in a manner analogous to Intermediate 3above. ¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 7.82 (2H, m), 7.63 (1H, s),7.28 (2H, m), 5.19 (2H, s), 3.01 (3H, m), 2.54 (3H, m), 1.92 (2H, m),1.54 (2H, m).

Preparation of Intermediate 5:4-[4-(2-Fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine

Intermediate 5 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 6:4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

Intermediate 6 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 7:4-[4-(3-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

Intermediate 7 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 8:4-[4-(2,6-Difluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

Intermediate 8 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 9:4-[4-(4-Pyrrol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

Intermediate 9 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 10:(2-Piperidin-4-yl-thiazol-4-ylmethyl)-(4-tetrazol-1-yl-phenyl)-amine

Intermediate 10 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 11:4-[4-(2-Methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

Intermediate 11 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 12:4-[4-(2-Isopropyl-5-methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

Intermediate 12 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 13:4-[4-(2-Chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

Intermediate 13 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 14:4-(4-Chloromethyl-oxazol-2-yl)-piperidine-1-carboxylic acid tert-butylester

A mixture of 4-(4-Hydroxymethyl-wxazol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (800 mg, 2.84 mmol) (obtained by the reduction of4-(4-Ethoxycarbonyl-oxazol-2-yl)-piperidine-1-carboxylic acid tert-butylester which was synthesized according to U.S. Patent Publication No.2006/0135501 A1), TsCl (812 mg, 4.26 mmol) and triethylamine (1 mL, 752mg, 7.44 mmol) in dichloromethane (20 mL) was stirred at roomtemperature for 5 hours. The resulting solution was washed successivelywith 5% NaHSO₃, saturated NaHCO₃, and brine. After drying (Na₂SO₄), thesolvent was removed to afford the desired product. ¹H NMR (CDCl₃): δ7.53 (s, 1H), 4.40 (s, 2H), 4.06 (m, 2H), 2.89 (m, 3H), 1.98 (m, 2H),1.74 (m, 2H), 1.41 (s, 9H).

Preparation of Intermediate 15:4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-oxazol-2-yl]-piperidine

Intermediate 15 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 16:4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-oxazol-2-yl]-piperidine

Intermediate 16 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 17:5-(2-Piperidin-4-yl-thiazol-4-ylmethoxy)-2-tetrazol-1-yl-pyridine

Intermediate 17 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 18:(6-Fluoro-pyridin-3-yl)-(2-piperidin-4-yl-thiazol-4-ylmethyl)-amine

Intermediate 18 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 19:4-[4-(2,6-Difluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine

Intermediate 19 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 20:4-[4-(2-Piperidin-4-yl-thiazol-4-ylmethoxy)-phenyl]-morpholine

Intermediate 20 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 21:4-[4-(2-Piperidin-4-yl-thiazol-4-ylmethoxy)-phenyl]-morpholine

Intermediate 21 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 22:4-(4-Chloromethyl-thiazol-2-yl)-3-methyl-piperidine-1-carboxylic acidtert-butyl ester

Intermediate 22 was prepared in a manner analogous to Intermediate 1above.

Preparation of Intermediate 23:3-Methyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

Intermediate 23 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 24:4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl-piperidine

Intermediate 24 was prepared in a manner analogous to Intermediate 3above.

Preparation of Intermediate 25:4-[4-(4-Methanesulfonyl-benzyloxymethyl)-thiazol-2-yl]-piperidine

Intermediate 25 was prepared in a manner analogous to Intermediate 3above.

Example 14-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of 4-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (Intermediate 1, 463 mg, 1.46 mmol),4-methanesulfonyl-phenol (252 mg, 1.46 mmol) and K₂CO₃ (404 mg, 2.92mmol) in acetone (25 mL) was heated under reflux overnight. Aftercooling, the solid was filtered through a pad of celite. The filtratewas concentrated in vacuo. The residue was purified on silica gel(EtOAc-hexanes, 1:1) to afford the desired product. ¹H NMR (CDCl₃): δ7.88 (2H, d, J=8.8 Hz), 7.23 (1H, s), 7.12 (2H, d, J=8.8 Hz), 5.24 (2H,s), 4.21 (2H, br), 3.17 (1H, m), 3.04 (3H, s), 2.88 (2H, m), 2.11 (2H,m), 1.73 (2H, m), 1.47 (9H, s).

The compounds in Examples 2-19 were synthesized from4-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butylester (Intermediate 1),2-[4-(4-Chloromethyl-thiazol-2-yl)-piperidin-1-yl]-5-ethyl-pyrimidine(Intermediate 2), 4-(4-Chloromethyl-oxazol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (Intermediate 14) or with the correspondingphenol, thiophenol, amine or aniline in a similar manner to thatdescribed in Example 1. One skilled in the art of organic synthesis willappreciate that conditions such as solvent (e.g., DMF, CH₃CN);temperature, base (e.g., NEt₃, K₂CO₃, NaHCO₃, Na₂CO₃, Cs₂CO₃) andconcentration can be selected through routine experimentation tooptimize yields. Additionally, alternative coupling methods can be usedthat are well known in the art of organic synthesis.

Example 24-[4-(4-Imidazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (DMSO-d₆): δ 8.12 (1H, s), 7.63 (2H, m), 7.54 (2H, d, J=9.2 Hz),7.15 (2H, d, J=9.2 Hz), 7.05 (1H, s), 5.15 (2H, s), 3.98 (2H, m), 3.21(1H, m), 2.87 (2H, m), 2.01 (2H, m), 1.52 (2H, m), 1.39 (9H, s).

Example 34-[4-(4-Acetylamino-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (DMSO-d₆): δ 9.77 (1H, s), 7.57 (1H, s), 7.45 (2H, d, J=9.0 Hz),6.94 (2H, d, J=9.0 Hz), 5.04 (2H, s), 3.98 (2H, m), 3.18 (1H, m), 2.82(2H, m), 2.02 (2H, m), 1.99 (3H, s), 1.51 (2H, m), 1.39 (9H, s).

Example 44-[4-(4-Methoxy-benzenesulfonyloxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.60 (2H, d, J=9.0 Hz), 7.24 (1H, s), 6.91 (2H, d,J=9.0 Hz), 4.50 (2H, s), 4.10 (2H, m), 3.85 (3H, s), 2.99 (1H, m), 2.82(2H, m), 1.89˜1.92 (2H, m), 1.53˜1.57 (2H, m), 1.46 (9H, s).

Example 54-[4-(4-[1,2,4]Triazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 8.47 (1H, s), 8.08 (1H, s), 7.58 (2H, d, J=9.2 Hz),7.24 (1H, s), 7.11 (2H, d, J=9.2 Hz), 5.21 (2H, s), 4.2 (2H, m), 3.18(1H, m), 2.88 (2H, m), 2.11 (2H, m), 1.74 (2H, m), 1.47 (9H, s).

Example 64-{4-[4-(2-oxo-pyrrolidin-1-yl)-phenoxymethyl]-thiazol-2-yl}-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.50 (2H, d), 7.20 (1H, s), 6.98 (2H, d), 5.17 (2H,s), 4.20 (2H, br), 3.81 (2H, m), 3.18 (1H, m), 2.88 (2H, m), 2.59 (2H,m), 2.16 (4H, m), 1.73 (2H, m), 1.46 (9H, s).

Example 74-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 8.94 (1H, s), 7.61 (2H, d), 7.25 (1H, s), 7.19 (2H,d), 5.21 (2H, s), 4.20 (2H, br), 3.20 (1H, m), 2.90 (2H, m), 2.16 (2H,m), 1.77 (2H, m), 1.49 (9H, s).

Example 84-[4-(4-Methanesulfonyl-phenylsulfanylmethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.7 (2H, d, J=9.0 Hz), 7.36 (2H, d, J=9.0 Hz), 7.00(1H, s), 4.24 (2H, s), 4.3 (2H, m), 3.05 (1H, m), 2.95 (3H, s), 2.78(2H, m), 1.99 (2H, m), 1.62 (2H, m), 1.38 (9H, s).

Example 94-{2-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yl]-thiazol-4-ylmethoxy}-benzenesulfonamide

¹H NMR (DMSO-d₆): δ 8.24 (2H, s), 7.73 (2H, d), 7.64 (1H, s), 7.20 (4H,m), 5.18 (2H, s), 4.67 (2H, m), 3.38 (1H, m), 3.01 (2H, m), 2.47 (2H,m), 2.08 (2H, m), 1.62 (2H, m), 1.53 (3H, m).

Example 102-{4-[4-(2,6-Dichloro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-5-ethyl-pyrimidine

¹H NMR (DMSO-d₆): δ 8.23 (2H, s), 7.99 (2H, s), 7.68 (1H, s), 5.20 (2H,s), 4.64 (2H, m), 3.31 (3H, s), 3.30 (1H, m), 3.0 (2H, m), 2.40 (2H, m),1.98 (2H, m), 1.54 (2H, m), 1.15 (3H, m).

Example 115-Ethyl-2-{4-[4-(3-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 9.05 (1H, s), 8.19 (2H, s), 7.55-7.10 (5H, m), 5.24(2H, s), 4.83 (2H, m), 3.30 (1H, m), 3.04 (2H, m), 2.47 (2H, q, J=7.6Hz), 2.21 (2H, m), 1.80 (2H, m), 1.19 (3H, t, J=7.6 Hz).

Example 125-Ethyl-2-(4-{4-[4-(5-methyl-tetrazol-1-yl)-phenoxymethyl]-thiazol-2-yl}-piperidin-1-yl)-pyrimidine

¹H NMR (CDCl₃): δ 8.19 (2H, s), 7.38 (2H, d, J=9.0 Hz), 7.26 (1H, s),7.17 (2H, d, J=9.0 Hz), 5.24 (2H, s), 4.84 (2H, m), 3.31 (1H, m), 3.05(2H, m), 2.58 (3H, s), 2.47 (2H, q, J=7.8 Hz), 2.22 (2H, m), 1.82 (2H,m), 1.20 (3H, t, J=7.8 Hz).

Example 135-Ethyl-2-{4-[4-(3-methyl-4-methylsulfanyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (DMSO-d₆): δ 8.23 (2H, s), 7.56 (1H, s), 7.16 (1H, m), 6.90 (1H,m), 6.86 (1H, m), 5.06 (2H, s), 4.67 (2H, m), 3.55 (4H, m), 3.01 (2H,m), 2.48 (3H, s), 2.40 (2H, m), 2.09 (2H, m), 1.57 (2H, m), 1.09 (3H,m).

Example 145-Ethyl-2-{4-[4-(4-methanesulfonyl-3-methyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (DMSO-d₆): δ 8.13 (2H, s), 7.91 (1H, m), 7.20 (1H, s), 6.85 (2H,m), 5.14 (2H, s), 4.76 (2H, m), 3.23 (1H, m), 2.98 (3H, s), 2.60 (3H,s), 2.42 (2H, m), 2.15 (2H, m), 1.97 (2H, m), 1.76 (2H, m), 1.13 (3H,m).

Example 156-{2-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yl]-thiazol-4-ylmethoxy}-benzo[1,3]oxathiol-2-one

¹H NMR (DMSO-d₆): δ 8.23 (2H, s), 7.64 (1H, m), 7.62 (1H, s), 7.30 (1H,m), 7.03 (1H, m), 5.14 (2H, s), 4.64 (2H, m), 3.31 (1H, m), 3.02 (2H,m), 2.40 (2H, q), 2.09 (2H, m), 1.58 (2H, m), 1.12 (3H, t).

Example 165-Ethyl-2-{4-[4-(4-trifluoromethylsulfanyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (DMSO-d₆): δ 8.23 (2H, s), 7.63 (3H, m), 7.18 (2H, m), 5.17 (2H,s), 4.67 (2H, m), 3.32 (1H, m), 3.01 (2H, m), 2.40 (2H, q), 2.08 (2H,m), 1.59 (2H, m), 1.13 (3H, t).

Example 174-[4-(3-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 9.04 (1H, s), 7.79 (1H, m), 7.29 (1H, s), 7.01 (2H,m), 5.24 (2H, s), 4.22 (2H, m), 3.19 (1H, m), 2.89 (2H, m), 2.11 (2H,m), 1.74 (2H, m), 1.48 (9H, s).

Example 184-[4-(2-Fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (DMSO-d₆): δ 7.79 (1H, m), 7.72 (1H, m), 7.70 (1H, s), 7.57 (1H,m), 5.31 (2H, s), 3.99 (2H, m), 3.21 (3H, s), 3.20 (1H, m), 2.85 (2H,m), 2.02 (2H, m), 1.52 (2H, m), 1.39 (9H, s).

Example 194-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 8.98 (s, 1H), 7.53 (m, 1H), 7.44 (m, 1H), 7.31 (s,1H), 7.27 (m, 1H), 5.31 (s, 2H), 4.21 (m, 2H), 3.16 (m, 1H), 2.89 (m,2H), 2.11 (m, 2H), 1.74 (m, 2H), 1.47 (s, 9H).

Example 205-Ethyl-2-{4-[4-(4-trifluoromethanesulfinyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

To a solution of5-Ethyl-2-{4-[4-(4-trifluoromethylsulfanyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine(Example 16) in DCM at room temperature was added3-chloro-benzenecarboperoxoic acid (2 eq.). The reaction was allowed tostir for 1.5 hours and an additional portion of3-chloro-benzenecarboperoxoic acid (1 eq.) was added to the reactionmixture. The reaction was stirred at room temperature for an additional4 hours. The organic solution was washed with sodium bicarbonate; theorganic layer was isolated, dried over sodium sulfate and filtered. Thefiltrate was concentrated and the crude product was purified by columnchromatography to afford the desired product. ¹H NMR (DMSO-d₆): δ 8.40(2H, s), 7.58 (2H, d), 7.22 (1H, s), 7.02 (2H, d), 5.17 (2H, s), 3.74(2H, m), 3.16 (1H, m), 2.96 (2H, m), 2.57 (2H, m), 2.22 (4H, m), 1.24(3H, m).

Example 214-[4-(4-Methanesulfonyl-benzenesulfonylmethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-[4-(4-Methanesulfonyl-phenylsulfanylmethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (Example 8, 0.1 g, 0.21 mmol) in CH₂Cl₂ (5 mL) wasadded mCPBA (0.11 g, 0.42 mmol) at room temperature. The resultingmixture was stirred at room temperature for 2 hours and was washed with5% NaHSO₃, saturated NaHCO₃ and brine. The organic layer was dried withNa₂SO₄ and the solvent was removed in vacuo. The residue was purified byflash chromatography on silica gel to afford the desired product. ¹H NMR(CDCl₃): δ 8.03 (2H, d, J=9.0 Hz), 7.88 (2H, d, J=9.0 Hz), 7.29 (1H, s),4.57 (2H, s), 4.10 (2H, m), 3.07 (3H, s), 2.92 (1H, m), 2.75 (2H, m),1.85 (2H, m), 1.46 (2H, m), 1.44 (9H, s).

Example 224-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid isopropyl ester

To the HCl salt (Intermediate 3, 43 mg, ˜0.12 mmol) of4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine wasadded 3 mL of THF, followed by isopropyl chloroformate (1.0 M solutionin toluene, 0.15 mL, 0.15 mmol) and Et₃N (0.05 mL). The resultingmixture was stirred at room temperature for 2 hours, and thenpartitioned between EtOAc and H₂O. After concentration of the organiclayer in vacuo, the residue was purified by silica gel columnchromatography with EtOAc/hexanes (40-70%) to give the desired product.¹H NMR (CDCl₃): δ 7.86 (2H, d, J=9.0 Hz), 7.23 (1H, s), 7.11 (2H, d,J=9.0 Hz), 5.22 (2H, s), 4.92 (1H, m), 4.24 (2H, m), 3.17 (1H, m), 3.03(3H, s), 2.90 (2H, m), 2.10 (2H, m), 1.72 (2H, m), 1.23 (6H, d, J=6.4Hz).

The compounds in Examples 23-46 were synthesized from one ofIntermediates 3-13 or Intermediates 15-25 with the correspondingsulfonyl chloride, alkyl chloride, alkyl bromide, chloroformate, acidchloride, carbamyl chloride or isocyanate in a manner similar to thatdescribed in Example 22. One skilled in the art of organic synthesiswill appreciate that conditions such as solvent (e.g., DMF, CH₃CN);temperature, base (e.g., NEt₃, K₂CO₃, NaHCO₃, Na₂CO₃, Cs₂CO₃) andconcentration can be selected through routine experimentation tooptimize yields. Additionally, alternative coupling methods can be usedthat are well known in the art of organic synthesis.

Example 234-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid benzyl ester

¹H NMR (CDCl₃): δ 7.87 (2H, d, J=9.2 Hz), 7.31˜7.37 (5H, m), 7.23 (1H,s), 7.11 (2H, d, J=9.2 Hz), 5.22 (2H, s), 5.14 (2H, s), 4.29 (2H, m),3.16˜3.22 (1H, m), 3.03 (3H, s), 2.96 (2H, m), 2.12 (2H, m), 1.70˜1.80(2H, m).

Example 244-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid isobutyl ester

¹H NMR (CDCl₃): δ 7.87 (2H, d, J=9.0 Hz), 7.23 (1H, s), 7.11 (2H, d,J=9.0 Hz), 5.22 (2H, s), 4.25 (2H, m), 3.87 (2H, d, J=6.6 Hz), 3.17 (1H,m), 3.03 (3H, s), 2.94 (2H, m), 2.12 (2H, m), 1.94 (1H, m), 1.75 (2H,m), 0.93 (6H, d, J=6.6 Hz).

Example 254-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid adamantan-1-yl ester

¹H NMR (CDCl₃): δ 7.89 (2H, d, J=8.8 Hz), 7.24 (1H, s), 7.12 (2H, d,J=8.8 Hz), 5.23 (2H, s), 4.21 (2H, m), 3.12˜3.20 (1H, m), 3.03 (3H, s),2.87 (2H, m), 2.05˜2.17 (11H, m), 1.62˜1.79 (8H, m).

Example 264-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid methyl ester

¹H NMR (CDCl₃): δ 7.87 (2H, d, J=9.0 Hz), 7.23 (1H, s), 7.11 (2H, d,J=9.0 Hz), 5.22 (2H, s), 4.24 (2H, m), 3.71 (3H, s), 3.14˜3.17 (1H, m),3.03 (3H, s), 2.94 (2H, m), 2.12 (2H, m), 1.70˜1.80 (2H, m).

Example 274-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid 4-fluoro-phenyl ester

¹H NMR (CDCl₃): δ 7.88 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz),7.01˜7.09 (5H, m), 5.24 (2H, s), 4.37 (2H, m), 3.23˜3.27 (1H, m), 3.19(2H, m), 3.04 (3H, s), 2.20 (2H, m), 1.88 (2H, m).

Example 284-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid 4-methoxy-phenyl ester

¹H NMR (CDCl₃): δ 7.88 (2H, d, J=8.2 Hz), 7.26 (1H, s), 7.12 (2H, d,J=8.6 Hz), 7.02 (2H, d, J=8.6 Hz), 6.87 (2H, d, J=8.2 Hz), 5.24 (2H, s),4.38 (2H, m), 3.79 (3H, s), 3.15˜3.28 (3H, m), 3.03 (3H, s). 2.19 (2H,m), 1.87 (2H, m).

Example 294-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid naphthalen-1-yl ester

¹H NMR (CDCl₃): δ 7.88 (4H, m), 7.72 (1H, m), 7.49 (3H, m), 7.29 (2H,m), 7.14 (2H, m), 5.26 (2H, s), 4.64 (1H, m), 4.41 (1H, m), 3.34 (2H,m), 3.12 (1H, m), 3.04 (3H, s), 2.27 (2H, m), 2.00 (2H, m).

Example 304-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid isobutyl ester

¹H NMR (CDCl₃): δ 8.94 (1H, s), 7.60 (2H, d), 7.24 (1H, s), 7.14 (2H,d), 5.20 (2H, s), 4.24 (2H, br), 3.85 (2H, d), 3.18 (1H, m), 2.92 (2H,m), 2.11 (2H, m), 1.91 (1H, m), 1.75 (2H, m), 0.91 (6H, d).

Example 314-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid pentyl ester

¹H NMR (CDCl₃): δ 8.94 (1H, s), 7.62 (2H, d, J=9.2 Hz), 7.28 (1H, s),7.18 (2H, d, J=9.2 Hz), 5.24 (2H, s), 4.27 (2H, br), 4.09 (2H, m), 3.21(1H, m), 2.94 (2H, m), 2.14 (2H, m), 1.78 (2H, m), 1.65 (2H, m), 1.35(4H, m), 0.91 (3H, m).

Example 324-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid 2-fluoro-ethyl ester

¹H NMR (CDCl₃): δ 8.97 (1H, s), 7.62 (2H, d, J=9.0 Hz), 7.28 (1H, s),7.17 (2H, d, J=9.0 Hz), 5.24 (2H, s), 4.70-4.30 (6H, m), 3.22 (1H, m),2.99 (2H, m), 2.15 (2H, m), 1.78 (2H, m).

Example 334-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid butyl ester

¹H NMR (CDCl₃): δ 9.01 (1H, s), 7.64 (2H, d, J=8.8 Hz), 7.29 (1H, s),7.17 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.26 (2H, m), 4.10 (2H, t), 3.21(1H, m), 2.95 (2H, m), 2.14 (2H, m), 1.78 (2H, m), 1.63 (2H, m), 1.40(2H, m), 0.95 (3H, t, J=7.4 Hz).

Example 344-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid 2,2-dimethyl-propyl ester

¹H NMR (CDCl₃): δ 9.00 (1H, s), 7.56 (2H, d, J=8.8 Hz), 7.21 (1H, s),7.08 (2H, d, J=8.8 Hz), 5.14 (2H, s), 4.17 (2H, br), 3.69 (2H, s), 3.13(1H, m), 2.88 (2H, m), 2.06 (2H, m), 1.73 (2H, m), 0.86 (9H, s).

Example 354-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid hexyl ester

¹H NMR (CDCl₃): δ 9.06 (1H, s), 7.65 (2H, d, J=8.8 Hz), 7.29 (1H, s),7.18 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.27 (2H, br), 4.09 (2H, t), 3.21(1H, m), 2.95 (2H, m), 2.14 (2H, m), 1.78 (2H, m), 1.64 (2H, m), 1.33(6H, m), 0.89 (3H, m).

Example 364-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid 2-ethyl-hexyl ester

¹H NMR (CDCl₃): δ 8.98 (1H, s), 7.58 (2H, d, J=8.8 Hz), 7.23 (1H, s),7.10 (2H, d, J=8.8 Hz), 5.17 (2H, s), 4.19 (2H, br), 3.95 (2H, m), 3.15(1H, m), 2.89 (2H, m), 2.07 (2H, m), 1.69 (2H, m), 1.52 (1H, m),1.35-1.20 (8H, m), 0.90-0.80 (6H, m).

Example 374-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid 2-benzyloxy-ethyl ester

¹H NMR (CDCl₃): δ 8.98 (1H, s), 7.57 (2H, d, J=8.0 Hz), 7.30-7.20 (6H,m), 7.11 (2H, d, J=8.0 Hz), 5.17 (2H, s), 4.52 (2H, s), 4.25-4.20 (4H,m), 3.65 (2H, m), 3.15 (1H, m), 2.91 (2H, m), 2.08 (2H, m), 1.73 (2H,m).

Example 384-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid 2-isopropyl-5-methyl-cyclohexyl ester

¹H NMR (CDCl₃): δ 8.97 (1H, s), 7.58 (2H, m), 7.23 (1H, s), 7.11 (2H,m), 5.18 (2H, s), 4.21 (2H, br), 3.13 (1H, m), 2.88 (2H, m), 2.05-0.70(23H, m).

Example 39

Adamantan-1-yl-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-methanone

¹H NMR (CDCl₃): δ 7.88 (2H, d, J=8.8 Hz), 7.24 (1H, s), 7.12 (2H, d,J=8.8 Hz), 5.23 (2H, s), 4.61 (2H, m), 3.24˜3.30 (1H, m), 3.03 (3H, s),2.93˜3.00 (2H, m), 2.16 (2H, m), 2.02˜2.04 (9H, m), 1.70-1.80 (8H, m).

Example 40{4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyridin-3-yl-methanone

¹H NMR (CDCl₃): δ 8.69 (2H, m), 7.88 (2H, d, J=8.4 Hz), 7.79 (1H, m),7.38 (1H, m), 7.27 (1H, s), 7.12 (2H, d, J=8.4 Hz), 5.24 (2H, s), 4.79(2H, br), 3.86 (2H, br), 3.31 (1H, m), 3.04 (3H, s), 2.20 (2H, m), 1.84(2H, m).

Example 413,3-Dimethyl-1-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-butan-1-one

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 7.81 (2H, d, J=8.8 Hz), 7.66 (1H, s),7.29 (2H, d, J=8.8 Hz), 5.20 (2H, s), 4.52 (1H, m), 4.10 (1H, m), 3.26(1H, m), 3.19 (1H, m), 2.70 (1H, m), 2.25 (2H, m), 2.15 (2H, m), 1.50(2H, m), 0.96 (9H, s).

Example 42Oxo-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-aceticacid methyl ester

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 7.81 (2H, d, J=8.8 Hz), 7.68 (1H, s),7.29 (2H, d, J=8.8 Hz), 5.21 (2H, s), 4.32 (1H, m), 3.80 (3H, s), 3.60(1H, m), 3.32 (1H, m), 2.94 (2H, m), 2.13 (2H, m), 1.57 (2H, m).

Example 433-oxo-3-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-propionicacid ethyl ester

¹H NMR (DMSO-d₆): δ 8.94 (1H, s), 7.61 (2H, m), 7.26 (1H, s), 7.15 (2H,m), 5.20 (2H, s), 4.65 (1H, m), 4.17 (2H, q), 3.87 (1H, m), 3.48 (2H,s), 3.26 (2H, m), 2.81 (1H, m), 2.18 (2H, m), 1.78 (2H, m), 1.27 (3H,t).

Example 44(4-Methyl-piperazin-1-yl)-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-methanone

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 7.81 (2H, d, J=8.9 Hz), 7.64 (1H, s),7.29 (2H, d), 5.20 (2H, s), 3.29 (2H, m), 3.18 (5H, m), 2.95 (2H, d),2.61 (3H, s), 2.38 (2H, m), 2.03 (4H, m), 1.65 (2H, m).

Example 454-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid diethylamide

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 7.81 (2H, d, J=8.9 Hz), 7.66 (1H, s),7.29 (2H, d, J=8.9 Hz), 5.20 (2H, s), 3.55 (2H, m), 3.20 (1H, m), 3.14(4H, q), 2.81 (2H, m), 2.02 (2H, m), 1.64 (2H, m), 1.02 (6H, t, J=6.8Hz).

Example 464-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid ethylamide

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 7.81 (2H, d, J=8.9 Hz), 7.65 (1H, s),7.29 (2H, d, J=8.9 Hz), 6.47 (1H, m), 5.20 (2H, s), 4.01 (2H, d), 3.17(1H, m), 3.04 (2H, m), 2.78 (2H, m), 1.97 (2H, m), 1.52 (2H, m), 0.99(3H, t, J=6.8 Hz).

Example 472-{4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

A mixture of4-[4-(4-methylsulfonyl-phenoxymethyl)-thiazole-2-yl]-piperidinehydrochloride (100 mg, 0.24 mmol), 2-chloropyrimidine (30 mg, 1.1 eq.)and diisopropylethylamine (122 mg, 4 eq.) in i-PrOH (5 mL) was heated at90° C. for 1.5 hours. The solvent was removed in vacuo. The residue waspurified on silica gel (60% EtOAc in hexanes) to afford the desiredproduct. ¹H NMR (CDCl₃): δ 8.32 (2H, d, J=4.8 Hz), 7.88 (2H, d, J=8.8Hz), 7.23 (1H, s), 7.12 (2H, d, J=8.8 Hz), 6.49 (1H, t, J=4.8 Hz), 5.24(2H, s), 4.89 (2H, m), 3.32 (1H, m), 3.06 (2H, m), 3.04 (3H, s), 2.22(2H, m), 1.81 (2H, m).

The compounds in Examples 48-77 were synthesized from one ofIntermediates 3-13 or Intermediates 15-25 with the correspondingsubstituted 2-chloropyrimidine, 2-iodopyrimidine, 2-chloropyridine,2-fluoropyridine, 2-methanesulfonyl-pyrimidine, 2-chloropyrazine,2-chloropyridazine or other suitable heterocycles in a manner similar tothat described in Example 47. One skilled in the art of organicsynthesis will appreciate that conditions such as solvent (such as DMF,CH₃CN); temperature, base (such as NEt₃, K₂CO₃, NaHCO₃, Na₂CO₃, Cs₂CO₃)and concentration can be selected through routine experimentation tooptimize yields. Additionally, alternative coupling methods can be usedthat are well known in the art of organic synthesis.

Example 482-{4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-4-methoxy-pyrimidine

¹H NMR (CDCl₃): δ 8.06 (1H, d, J=6.0 Hz), 7.87 (2H, d, J=8.8 Hz), 7.23(1H, s), 7.12 (2H, d, J=8.8 Hz), 5.98 (1H, d, J=6.0 Hz), 5.24 (2H, s),4.88 (2H, m), 3.90 (3H, s), 3.31 (1H, m), 3.04 (5H, m), 2.20 (2H, m),1.81 (2H, m).

Example 492-{4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-4-trifluoromethyl-pyrimidine

¹H NMR (CDCl₃): δ 8.50 (1H, d, J=4.8 Hz), 7.88 (2H, d, J=8.8 Hz), 7.24(1H, s), 7.12 (2H, d, J=8.8 Hz), 6.76 (1H, d, J=4.8 Hz), 5.24 (2H, s),4.92 (2H, m), 3.34 (1H, m), 3.11 (2H, m), 3.04 (3H, s), 2.24 (2H, m),1.84 (2H, m).

Example 502-{4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-4,6-dimethyl-pyrimidine

¹H NMR (CDCl₃): δ 7.88 (2H, d, J=8.4 Hz), 7.22 (1H, s), 7.12 (2H, d,J=8.4 Hz), 6.27 (1H, s), 5.24 (2H, s), 4.96 (2H, m), 3.28 (1H, m), 3.04(3H, s), 2.99 (2H, m), 2.29 (6H, s), 2.19 (2H, m), 1.80 (2H, m).

Example 515-Ethyl-2-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.19 (2H, s), 7.87 (2H, d, J=8.8 Hz), 7.22 (1H, s),7.12 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.84 (2H, m), 3.30 (1H, m), 3.04(2H, m), 3.03 (3H, s), 2.47 (2H, q, J=7.2 Hz), 2.22 (2H, m), 1.81 (2H,m), 1.20 (3H, t, J=7.2 Hz).

Example 525-Ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 8.24 (2H, s), 7.80 (2H, d, J=8.8 Hz),7.66 (1H, s), 7.28 (2H, d, J=8.8 Hz), 5.20 (2H, s), 4.67 (2H, m), 3.32(1H, m), 3.01 (2H, m), 2.43 (2H, q, J=7.2 Hz), 2.07 (2H, m), 1.59 (2H,m), 1.11 (3H, t, J=7.2 Hz).

Example 535-Fluoro-2-{4-[4-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (DMSO-d₆): δ 10.07 (1H, s), 8.43 (2H, s), 8.41 (1H, d, J=3.2 Hz),7.98 (1H, d, J=9.2 Hz), 7.86 (1H, dd, J=9.2, 3.2 Hz), 7.71 (1H, s), 5.30(2H, s), 4.58 (2H, m), 3.31 (1H, m), 3.01 (2H, m), 2.10 (2H, m), 1.59(2H, m).

Example 545-Bromo-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.90 (1H, s), 8.29 (2H, s), 7.60 (2H, d, J=9.0 Hz),7.25 (1H, s), 7.16 (2H, d, J=9.0 Hz), 5.23 (2H, s), 4.81 (2H, m), 3.31(1H, m), 3.06 (2H, m), 2.21 (2H, m), 1.79 (2H, m).

Example 555-Fluoro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.91 (1H, s), 8.20 (2H, s), 7.60 (2H, d, J=8.6 Hz),7.25 (1H, s), 7.16 (2H, d, J=8.6 Hz), 5.23 (2H, s), 4.78 (2H, m), 3.31(1H, m), 3.06 (2H, m), 2.21 (2H, m), 1.83 (2H, m).

Example 564,5-Dichloro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.91 (1H, s), 8.10 (1H, s), 7.61 (2H, d, J=8.8 Hz),7.27 (1H, s), 7.16 (2H, d, J=8.8 Hz), 5.23 (2H, s), 4.62 (2H, m), 3.34(1H, m), 3.18 (2H, m), 2.25 (2H, m), 1.98 (2H, m).

Example 574-Chloro-5-methyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.90 (1H, s), 8.08 (1H, s), 7.60 (2H, d, J=8.8 Hz),7.24 (1H, s), 7.17 (2H, d, J=8.8 Hz), 5.23 (2H, s), 4.80 (2H, m), 3.30(1H, m), 3.04 (2H, m), 2.19 (2H, m), 2.16 (3H, s), 1.81 (2H, m).

Example 582-Chloro-5-methyl-4-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.92 (1H, s), 7.96 (1H, s), 7.60 (2H, d, J=8.8 Hz),7.27 (1H, s), 7.16 (2H, d, J=8.8 Hz), 5.23 (2H, s), 4.17 (2H, m), 3.31(1H, m), 3.10 (2H, m), 2.26 (2H, m), 2.21 (3H, s), 1.95 (2H, m).

Example 595-(4-Chloro-phenyl)-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (DMSO-d₆): δ 9.97 (1H, s), 8.71 (2H, s), 7.80 (2H, d, J=8.8 Hz),7.67 (2H, d, J=8.4 Hz), 7.66 (1H, s), 7.48 (2H, d, J=8.4 Hz), 7.28 (2H,d, J=8.8 Hz), 5.21 (2H, s), 4.76 (2H, m), 3.37 (1H, m), 3.13 (2H, m),2.12 (2H, m), 1.66 (2H, m).

Example 605-Chloro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.91 (1H, s), 8.23 (2H, s), 7.61 (2H, d, J=8.8 Hz),7.26 (1H, s), 7.17 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.82 (2H, m), 3.32(1H, m), 3.07 (2H, m), 2.22 (2H, m), 1.81 (2H, m).

Example 615-Heptyl-2-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.16 (2H, s), 7.87 (2H, d, J=9.0 Hz), 7.22 (1H, s),7.12 (2H, d, J=9.0 Hz), 5.24 (2H, s), 4.83 (2H, m), 3.29 (1H, m), 3.04(2H, m), 3.03 (3H, s), 2.42 (2H, t, J=7.4 Hz), 2.21 (2H, m), 1.80 (2H,m), 1.52 (2H, m), 1.28 (8H, m), 0.89 (3H, t).

Example 622-{4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-5-pentyl-pyrimidine

¹H NMR (CDCl₃): δ 8.16 (2H, s), 7.87 (2H, d, J=8.8 Hz), 7.22 (1H, s),7.12 (2H, d, J=8.8 Hz), 5.23 (2H, s), 4.83 (2H, m), 3.29 (1H, m), 3.04(2H, m), 3.03 (3H, s), 2.42 (2H, t, J=7.6 Hz), 2.21 (2H, m), 1.81 (2H,m), 1.56 (2H, m), 1.32 (4H, m), 0.90 (3H, t).

Example 635-Heptyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.90 (1H, s), 8.16 (2H, s), 7.60 (2H, d, J=8.8 Hz),7.24 (1H, s), 7.17 (2H, d, J=8.8 Hz), 5.23 (2H, s), 4.82 (2H, m), 3.29(1H, m), 3.04 (2H, m), 2.42 (2H, t), 2.20 (2H, m), 1.80 (2H, m), 1.53(2H, m), 1.28 (8H, m), 0.87 (3H, t).

Example 645-Pentyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.90 (1H, s), 8.16 (2H, s), 7.60 (2H, d, J=8.8 Hz),7.24 (1H, s), 7.17 (2H, d, J=8.8 Hz), 5.23 (2H, s), 4.83 (2H, m), 3.30(1H, m), 3.04 (2H, m), 2.42 (2H, t), 2.20 (2H, m), 1.80 (2H, m), 1.54(2H, m), 1.30 (4H, m), 0.89 (3H, t).

Example 655-Methyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.94 (1H, s), 8.17 (2H, s), 7.62 (2H, d, J=8.8 Hz),7.25 (1H, s), 7.17 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.82 (2H, d), 3.30(1H, m), 3.04 (2H, m), 2.22 (2H, m), 2.13 (3H, s), 1.81 (2H, m).

Example 665-(4-Methoxy-phenyl)-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.90 (1H, s), 8.52 (s, 2H), 7.61 (2H, d, J=9.0 Hz),7.41 (2H, d, J=8.6 Hz), 7.25 (1H, s), 7.17 (2H, d, J=9.0 Hz), 6.99 (2H,d, J=8.6 Hz), 5.24 (2H, s), 4.92 (2H, m), 3.85 (3H, s), 3.34 (1H, m),3.12 (2H, m), 2.25 (2H, m), 1.85 (2H, m).

Example 675-Propyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.9 (1H, s), 8.17 (2H, s), 7.61 (2H, d, J=8.8 Hz),7.24 (1H, s), 7.17 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.83 (2H, m), 3.31(1H, m), 3.04 (2H, m), 2.4 (2H, t, J=7.6 Hz), 2.22 (2H, m), 1.81 (2H,m), 1.58 (2H, m), 0.94 (3H, t, J=7.6 Hz).

Example 685-Methoxy-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.93 (1H, s), 8.11 (2H, s), 7.61 (2H, d, J=8.8 Hz),7.25 (1H, s), 7.17 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.74 (2H, m), 3.81(3H, s), 3.31 (1H, m), 3.03 (2H, m), 2.22 (2H, m), 1.82 (2H, m).

Example 695′-Methyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

¹H NMR (CDCl₃): δ 8.91 (1H, s), 8.03 (1H, m), 7.61 (2H, m), 7.33 (1H,m), 7.26 (1H, s), 7.18 (2H, m), 6.65 (1H, d, J=8.8 Hz), 5.24 (2H, s),4.33 (2H, m), 3.25 (1H, m), 2.97 (2H, m), 2.22 (2H, m), 2.21 (3H, s),1.89 (2H, m).

Example 704-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-5′,6″-bis-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′;6′,2″]terpyridine

¹H NMR (DMSO-d₆): δ 8.81 (1H, m), 8.39 (1H, m), 8.13 (1H, dd, J=8.8, 2.4Hz), 7.76 (1H, dd, J=8.8, 2.8 Hz), 7.66 (1H, s), 7.59 (2H, m), 7.25 (2H,m), 6.99 (1H, d, J=9 Hz), 6.8 (1H, d, J=9 Hz), 5.19 (2H, s), 4.48 (2H,d), 3.37 (1H, m), 3.10 (2H, m), 2.11 (2H, m), 1.65 (2H, m).

Example 714-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 8.40 (1H, m), 7.81-7.75 (3H, m), 7.66(1H, s), 7.28 (2H, d), 6.99 (1H, d, J=8.8 Hz), 5.21 (2H, s), 4.48 (2H,d), 3.37 (1H, m), 3.1 (2H, m), 2.12 (2H, m), 1.65 (2H, m).

Example 724-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbaldehyde

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 9.72 (1H, s), 8.58 (1H, d, J=2.4 Hz),7.86 (1H, dd, J=9.2, 2 Hz), 7.8 (2H, d, J=8.4 Hz), 7.67 (1H, s), 7.28(2H, d, J=8.4 Hz), 6.99 (1H, d, J=8.8 Hz), 5.2 (2H, s), 4.58 (2H, d),3.41 (1H, m), 3.17 (2H, m), 2.13 (2H, m), 1.65 (2H, m).

Example 731-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine

¹H NMR (CDCl₃): δ 7.87 (2H, m), 7.26 (1H, s), 7.11 (2H, m), 5.23 (2H,s), 4.76-4.68 (1H, m), 4.26-4.18 (1H, m), 3.4˜3.3 (2H, m), 3.2˜3.04 (2H,m), 3.03 (3H, s), 2.32-2.2 (2H, m), 2.00-1.86 (2H, m), 1.36 (6H, d,J=7.2 Hz).

Example 742-{4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-benzooxazole

¹H NMR (CDCl₃): δ 7.87 (2H, d, J=8.4 Hz), 7.36 (1H, d, J=7.6 Hz),7.01˜7.19 (6H, m), 5.24 (2H, s), 4.42 (2H, m), 3.30 (3H, m), 3.03 (3H,s), 2.27 (2H, m), 1.95 (2H, m).

Example 754-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

¹H NMR (CDCl₃): δ 8.4 (1H, s), 7.87 (2H, d), 7.63 (1H, m), 7.26 (1H, s),7.12 (2H, d), 6.69 (1H, d), 5.23 (2H, s), 4.55-4.50 (2H, m), 3.38-3.28(1H, m), 3.20-3.10 (2H, m), 3.04 (3H, s), 2.30-2.20 (2H, m), 1.90-1.80(2H, m).

Example 765-Ethyl-2-{4-[4-(2-fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.18 (2H, s), 7.65˜7.70 (2H, m), 7.21˜7.26 (2H, m),5.30 (2H, s), 4.81˜4.84 (2H, m), 3.25˜3.28 (1H, m), 3.03 (3H, s),3.00˜3.07 (2H, m), 2.44 (2H, q), 2.21 (2H, m), 1.77˜1.81 (2H, m), 1.19(3H, t).

Example 775-Ethyl-2-{4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.96 (1H, s), 8.19 (2H, s), 7.55-7.25 (4H, m), 5.31(2H, s), 4.82 (2H, m), 3.30 (1H, m), 3.04 (2H, m), 2.47 (2H, q), 2.23(2H, m), 1.81 (2H, m), 1.20 (3H, t).

Example 784-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-4-methyl-piperidine-1-carboxylicacid tert-butyl ester

Step 1: 4-Cyano-4-methyl-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4-cyano-piperidine-1-carboxylic acid tert-butyl ester(4.52 g, 20 mmol) in THF (50 mL) was added LHMDS in THF (24 mL, 24 mmol)at 0° C. After stirring at 0° C. for 1 hour, MeI (5.7 g) was added. Thereaction mixture was kept at 0° C. for 2 hours, then partitioned betweenEtOAc and H₂O. After concentration in vacuo, the residue was purified bysilica column chromatography with EtOAc/hexanes to give the desiredproduct.

Step 2: 4-Carbamoyl-4-methyl-piperidine-1-carboxylic acid tert-butylester

To a solution of 4-cyano-4-methyl-piperidine-1-carboxylic acidtert-butyl ester (2.24 g, 10 mmol) in methanol (25 mL) was added DMSO (1mL), aqueous 1N NaOH (12 mL, 12 mmol) and H₂O₂ (4 mL) at roomtemperature. The mixture was heated at 50° C. for 3 hours. After coolingto room temperature, the mixture was partitioned between EtOAc and H₂O.The organic layer was washed successively with H₂O and brine. Afterdrying (Na₂SO₄), the solvent was removed to afford the desired product.

Step 3: 4-Methyl-4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butylester

To a solution of 4-carbamoyl-4-methyl-piperidine-1-carboxylic acidtert-butyl ester (2.1 g, 8.7 mmol) in THF (30 mL) was added Lawesson'sreagent (3.5 g, 8.7 mmol) at room temperature. The mixture was heated at50° C. for 3 hours. After cooling to room temperature, the solvent wasremoved in vacuo and the residue was partitioned between EtOAc and H₂O.The organic layer was washed with saturated NaHCO₃, and brine. Afterdrying (Na₂SO₄), the solvent was removed in vacuo, and the residue waspurified by silica column chromatography with EtOAc/hexanes to affordthe desired product.

Step 4:4-(4-Ethoxycarbonyl-thiazol-2-yl)-4-methyl-piperidine-1-carboxylic acidtert-butyl ester

To a solution of 4-methyl-4-thiocarbamoyl-piperidine-1-carboxylic acidtert-butyl ester (1 g, 4 mmol) in EtOH (10 mL) was added ethylbromopyruvate (0.78 g, 4 mmol) at room temperature. The mixture washeated to refluxing for 3 hours. After cooling to room temperature, thesolvent was removed in vacuo. The residue was dissolved in methylenechloride (15 mL), Et₃N (1 mL) and di-tert-butyl dicarbonate (1.3 g) wereadded to the solution. The mixture was stirred at room temperatureovernight. The mixture was washed with H₂O and brine. After drying(Na₂SO₄), the solvent was removed in vacuo, and the residue was purifiedby silica column chromatography with EtOAc/hexanes to afford the desiredproduct.

Step 5:4-(4-Hydroxymethyl-thiazol-2-yl)-4-methyl-piperidine-1-carboxylic acidtert-butyl ester

To a solution of4-(4-ethoxycarbonyl-thiazol-2-yl)-4-methyl-piperidine-1-carboxylic acidtert-butyl ester (0.6 g, 1.7 mmol) in anhydrous THF (10 mL) was addedLiAlH₄ (0.1 g, 2.6 mmol) at 0° C. The mixture was kept at 0° C. for 2hours and the reaction was quenched with EtOH. The solvent wasevaporated and the residue was diluted with EtOAc, washed with 1N NaOH,brine. After drying (Na₂SO₄), the solvent was removed in vacuo, and theresidue was purified by silica column chromatography with EtOAc/hexanesto afford the desired product.

Step 6:4-(4-Methanesulfonyloxymethyl-thiazol-2-yl)-4-methyl-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-(4-hydroxymethyl-thiazol-2-yl)-4-methyl-piperidine-1-carboxylic acidtert-butyl ester (0.42 g, 1.3 mmol) in methylene chloride (10 mL) wasadded methanesulfonyl chloride (0.19 g, 1.7 mmol) and triethylamine (0.2g, 2 mmol) at 0° C. After stirring at 0° C. for 1 hour, the mixture wasdiluted with EtOAc and washed with H₂O and brine. After drying (Na₂SO₄),the solvent was removed in vacuo, and the residue was purified by silicacolumn chromatography with EtOAc/hexanes to afford the desired product.

Step 7:4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-4-methyl-piperidine-1-carboxylicacid tert-butyl ester

A mixture of4-(4-methanesulfonyloxymethyl-thiazol-2-yl)-4-methyl-piperidine-1-carboxylicacid tert-butyl ester (0.2 g, 0.5 mmol), 4-methanesulfonyl-phenol (86mg, 0.5 mmol) and Cs₂CO₃ (170 mg, 0.52 mmol) in acetonitrile (4 mL) washeated at 40° C. overnight. After cooling, the solid was filteredthrough a pad of celite. The filtrate was concentrated in vacuo. Theresidue was purified on silica gel (EtOAc-hexanes, 1:1) to afford thedesired product. ¹H NMR (CDCl₃): δ 7.83 (2H, m), 7.23 (1H, s), 7.09 (2H,m), 5.2 (2H, s), 3.64-3.54 (2H, m), 3.3˜3.24 (2H, m), 2.99 (3H, s),2.2˜2.1 (2H, m), 1.72-1.64 (2H, m), 1.41 (9H, s), 1.36 (3H, s).

Example 794-[4-(4-Methanesulfonyl-phenoxymethyl)-5-methyl-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-(4-hydroxymethyl-5-methyl-thiazol-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (0.18 g, 0.6 mmol), 4-methanesulfonyl-phenol (0.1 g,0.6 mmol) and PPh₃ (0.19 g, 0.72 mmol) in THF (5 mL) was addeddiethylazodicarboxylate (DEAD) (0.22 g, 0.72 mmol) at room temperature.The resulting mixture was stirred at room temperature for 30 minutes.The solvent was removed and the residue was purified by flashchromatography on silica gel to afford the desired product. ¹H NMR(CDCl₃): δ 7.9 (2H, d, J=9 Hz), 7.09 (2H, d, J=9 Hz), 5.2 (2H, s),4.28-4.10 (2H, m), 3.14-3.04 (1H, m), 3.04 (3H, s), 2.9-2.8 (2H, m),2.44 (3H, s), 2.1-2 (2H, m), 1.76-1.64 (2H, m), 1.47 (9H, s).

Example 804-{4-[1-(4-Methanesulfonyl-phenoxy)-ethyl]-5-methyl-thiazol-2-yl}-piperidine-1-carboxylicacid tert-butyl ester

Step 1:4-[4-(1-Hydroxy-ethyl)-5-methyl-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-(4-formyl-5-methyl-thiazol-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (0.31 g, 1 mmol) in THF (10 mL) was added MeMgI (1 mL,3 mmol) in Et₂O at room temperature. The resulting mixture was stirredat room temperature for 1 hour. The reaction was quenched with saturatedaqueous NH₄Cl and extracted with EtOAc. The organic layer was washedwith H₂O and brine. After drying over Na₂SO₄, the solvent was removed.The residue was purified by flash chromatography on silica gel to affordthe desired product.

Step 2:4-{4-[1-(4-Methanesulfonyl-phenoxy)-ethyl]-5-methyl-thiazol-2-yl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-[4-(1-Hydroxy-ethyl)-5-methyl-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (0.15 g, 0.46 mmol), 4-methanesulfonyl-phenol(0.08 g, 0.46 mmol) and PPh₃ (0.14 g, 0.55 mmol) in THF (5 mL) was addedDEAD (0.1 g, 0.55 mmol) at room temperature. The resulting mixture wasstirred at room temperature for 30 minutes. The solvent was removed. Theresidue was purified by flash chromatography on silica gel to afford thedesired product. ¹H NMR (CDCl₃): δ 7.79 (2H, m), 6.94 (2H, m), 5.59 (1H,q, J=6 Hz),), 4.2-4.04 (2H, m), 3.04-2.94 (1H, m), 2.98 (3H, s),2.86-2.72 (2H, m), 2.39 (3H, s), 2.04-1.96 (2H, m), 1.67 (3H, d, J=6Hz), 1.66-1.58 (2H, m), 1.42 (9H, s).

Example 814-[3-(4-Methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-5-yl]-piperidine-1-carboxylicacid tert-butyl ester

Step 1: N-Hydroxy-2-(4-methanesulfonyl-phenoxy)-acetamidine

To a mixture of (4-methanesulfonyl-phenoxy)-acetonitrile (2 g, 9.5mmol), K₂CO₃ (1.3 g, 9.5 mmol) in H₂O (30 mL) and EtOH (15 mL) was addedhydroxylamine hydrogenchloride (1.32 g, 19 mmol). The mixture was heatedunder reflux overnight, cooled and ethanol was removed in vacuo and theresidue was extracted with EtOAc (150 mL). The organic layer was washedsuccessively with H₂O and brine. After drying (Na₂SO₄), the solvent wasremoved to afford the desired product.

Step 2:4-[3-(4-Methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-5-yl]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester(2.06 g, 9 mmol), NEt₃ (1.2 g, 12 mmol) in toluene (150 mL) was addedisobutylchloroformate (1.23 g, 9 mmol) at 0° C. The mixture was stirredat room temperature for 1.5 hours.N-hydroxy-2-(4-methanesulfonyl-phenoxy)-acetamidine (1.5 g, 6 mmol) wasadded to the mixture. The mixture was heated under reflux overnight,cooled and the mixture was washed successively with H₂O and brine. Afterdrying (Na₂SO₄), the solvent was removed. The residue was purified byflash chromatography on silica gel to afford the desired product. ¹H NMR(CDCl₃): δ 7.98 (2H, m), 7.14 (2H, m), 5.24 (2H, s), 4.2-4.05 (2H, m),3.14 (1H, m), 3.03 (3H, s), 2.95 (2H, m), 2.12˜2.04 (2H, m), 1.80 (2H,m), 1.46 (9H, s).

Example 824-[5-(4-Methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-3-yl]-piperidine-1-carboxylicacid tert-butyl ester

Step 1: 4-(N-Hydroxycarbamimidoyl)-piperidine-1-carboxylic acidtert-butyl ester

To a mixture of 4-cyano-piperidine-1-carboxylic acid tert-butyl ester(6.3 g, 30 mmol), K₂CO₃ (4.2 g, 30 mmol) in H₂O (50 mL) and EtOH (30 mL)was added hydroxylamine hydrogenchloride (4.17 g, 60 mmol). The mixturewas heated under reflux overnight, cooled to room temperature andethanol was removed in vacuo. The residue was extracted with EtOAc (300mL). The organic layer was washed successively with H₂O and brine. Afterdrying (Na₂SO₄), the solvent was removed to afford the desired product.

Step 2:4-(5-Hydroxymethyl-[1,2,4]oxadiazol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester

To a solution of hydroxy-acetic acid (1.67 g, 22 mmol), NEt₃ (4.4 g, 44mmol) in toluene (150 mL) was added isobutylchloroformate (6 g, 44 mmol)at 0° C. The mixture was stirred at room temperature for 1.5 hours.4-(N-Hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester(5.35 g, 22 mmol) was added to the mixture. The mixture was heated underreflux overnight, and then cooled to room temperature; the mixture waswashed successively with H₂O and brine. After drying (Na₂SO₄), thesolvent was removed. The residue was dissolved in THF (20 mL), andaqueous NaOH (10 mL, 10 mmol) was added. The mixture was stirred at roomtemperature for 2 hours and diluted with EtOAc (50 mL). The organiclayer was washed with brine, after drying (Na₂SO₄), the solvent wasremoved in vacuo, and the residue was purified by silica columnchromatography with EtOAc/hexanes to afford the desired product.

Step 3:4-(5-Methanesulfonyloxymethyl-[1,2,4]oxadiazol-3-yl)-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-(5-hydroxymethyl-[1,2,4]oxadiazol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester (0.2 g, 0.7 mmol) in methylene chloride (5 mL) wasadded methanesulfonyl chloride (0.1 g, 0.9 mmol) and triethyl amine(0.14 g, 1.4 mmol) at 0° C. After stirred at 0° C. for 1 hour, themixture was diluted with EtOAc and washed with H₂O, brine. After drying(Na₂SO₄), the solvent was removed in vacuo, and the residue was purifiedby silica column chromatography with EtOAc/hexanes to afford the desiredproduct

Step 4:4-[5-(4-Methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-3-yl]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of4-(5-methanesulfonyloxymethyl-[1,2,4]oxadiazol-3-yl)-piperidine-1-carboxylicacid tert-butyl ester (0.12 g, 0.33 mmol), 4-methanesulfonyl-phenol (86mg, 0.5 mmol) and Cs₂CO₃ (0.33 g, 1 mmol) in acetonitrile (5 mL) washeated at 50° C. for 2 hours. After cooling, the solid was filteredthrough a pad of celite. The filtrate was concentrated in vacuo. Theresidue was purified on silica gel (EtOAc-hexanes, 1:1) to afford thedesired product. ¹H NMR (CDCl₃): δ 7.9 (2H, d, J=8.8 Hz), 7.12 (2H, d,J=8.8 Hz), 5.34 (2H, s), 4.2˜4.05 (2H, m), 3.03 (3H, s), 3.04˜2.85 (3H,m), 2.05˜1.96 (2H, m), 1.8˜1.7 (2H, m), 1.45 (9H, s).

Example 834-(5-Benzyloxymethyl-[1,2,4]oxadiazol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester

To a solution of benzyloxy-acetic acid (5 g, 30 mmol), NEt₃ (3.6 g, 36mmol) in toluene (150 mL) was added isobutylchloroformate (4.1 g, 30mmol) at 0° C. The mixture was stirred at room temperature for 1.5hours. 4-(N-hydroxycarbamimidoyl)-piperidine-1-carboxylic acidtert-butyl ester (7.3 g, 30 mmol) was added to the mixture. The mixturewas heated under reflux overnight, cooled and the mixture was washedsuccessively with H₂O and brine. After drying (Na₂SO₄), the solvent wasremoved. The residue was purified by flash chromatography on silica gelto afford the desired product. ¹H NMR (CDCl₃): δ 7.4˜7.3 (5H, m), 4.7(2H, s), 4.69 (2H, s), 4.2˜4.04 (2H, m), 3.02˜2.84 (3H, m), 2.04˜1.94(2H, m), 1.84˜1.7 (2H, m), 1.46 (9H, s).

Example 845-Ethyl-2-{4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-pyrimidine

To the crude HCl salt (0.18 g, ˜0.5 mmol) of4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-5-yl]-piperidine,prepared by treatment of4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-5-yl]-piperidine-1-carboxylicacid tert-butyl ester (Example 81) in dioxane with 4N HCl, was added2-propanol (3 mL), followed by DIPEA (0.13 g, 1 mmol) and2-Chloro-5-ethyl-pyrimidine (0.14 g, 1 mmol). The resulting mixture wasstirred at 70° C. overnight. After concentration in vacuo, the residuewas purified by silica column chromatography with EtOAc/hexanes toafford the desired product. ¹H NMR (CDCl₃): δ 8.18 (2H, s), 7.89 (2H, d,J=8.8 Hz), 7.15 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.75˜4.65 (2H, m),3.3˜3.2 (1H, m), 3.2˜3.1 (2H, m), 3.03 (3H, s), 2.47 (2H, q, J=7.6 Hz),2.22˜2.16 (2H, m), 1.96˜1.84 (2H, m), 1.19 (3H, t, J=7.6 Hz).

Example 854-Hydroxy-4-[4-(4-methylsulfanyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

Step 1: 4-(4-Methylsulfanyl-phenoxymethyl)-thiazole

A mixture of 4-chloromethyl thiazole hydrochloride (3.0 g, 17.6 mmol),4-methylsulfanyl-phenol (2.5 g, 1 eq.) and K₂CO₃ (6.1 g, 2.5 eq.) inacetone (60 mL) was heated to reflux for 48 hours. After cooling, thesolid was filtered off. The filtrate was evaporated to dryness in vacuo.The crude product was redissolved in diethyl ether. The solution waswashed twice with 2N NaOH solution and then with H₂O. After being driedover Na₂SO₄, removal of the solvent afforded the desired product as anoff-white solid.

Step 2:4-Hydroxy-4-[4-(4-methylsulfanyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

To a stirred solution of 4-(4-methanesulfanyl-phenoxymethyl)-thiazole(3.92 g, 16.5 mmol) in THF (40 mL) at −78° C. was added n-BuLi (1.73 mL,1.05 eq., 10.0 M in hexanes). The resulting solution was stirred at thistemperature for 30 minutes. Then a solution of 1-Boc-4-piperidone (3.30g, 1 eq.) in THF (20 mL) was added in dropwise. The resulting mixturewas stirred for 30 minutes. The reaction was quenched by addition of H₂O(5 mL). Most of the THF was removed in vacuo. The mixture was extractedwith EtOAc. The organic layer was separated, washed with brine and driedover Na₂SO₄. After removal of the solvent, the crude product waspurified on silica gel (EtOAc:hexanes=2:3) to afford the desired productas a foam. ¹H NMR (CDCl₃): δ 7.27 (2H, d, J=8.8 Hz), 7.26 (1H, s), 6.93(2H, d, J=8.8 Hz), 5.14 (2H, s), 4.02 (2H, br), 3.27 (2H, br), 2.97 (1H,br), 2.45 (3H, s), 2.11 (2H, m), 1.86 (2H, m), 1.48 (9H, s).

Example 864-Hydroxy-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-hydroxy-4-[4-(4-methylsulfanyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (Example 85, 6.8 g, 15.6 mmol) in CH₂Cl₂ (150 mL)at room temperature was added m-CPBA (8.4 g, 2.2 eq.) portionwise. Theresulting solution was stirred for 30 minutes, then it was washed with 2N NaOH solution twice and dried over Na₂SO₄. After removal of thesolvent, the crude product was purified on silica gel(EtOAc:hexanes=3:2) to afford the desired product as a white foam. ¹HNMR (CDCl₃): δ 7.88 (2H, d, J=8.8 Hz), 7.31 (1H, s), 7.12 (2H, d, J=8.8Hz), 5.24 (2H, s), 4.03 (2H, br), 3.27 (2H, br), 3.04 (3H, s), 2.13 (2H,m), 1.86 (2H, m), 1.48 (9H, s).

Example 874-Fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-hydroxy-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (Example 86, 5.29 g, 11.3 mmol) in CH₂Cl₂ (100 mL)at 0° C. was added DAST (1.8 mL, 1.2 eq.). The reaction mixture wasstirred for 30 minutes before it was quenched by addition of saturatedNaHCO₃ solution (20 mL). The organic phase was separated and dried overNa₂SO₄. After removal of the solvent, the crude product was purified onsilica gel (EtOAc:hexanes=2:3) to afford the desired product as a whitesolid. ¹H NMR (CDCl₃): δ 7.86 (2H, d, J=9.2 Hz), 7.35 (1H, s), 7.10 (2H,d, J=9.2 Hz), 5.22 (2H, s), 4.08 (2H, br), 3.19 (2H, br), 3.02 (3H, s),2.05˜2.32 (4H, m), 1.46 (9H, s).

Example 885-Ethyl-2-{4-fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

Step 1:4-Fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidinehydrochloride

To a solution of4-fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (Example 87, 4.24 g, 9.01 mmol) in methanol (50mL) was added 4 N HCl in dioxane (15 mL). The resulting solution wasstirred overnight. The mixture was then evaporated to dryness in vacuoto afford the desired product as a white solid.

Step 2:5-Ethyl-2-{4-fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

A solution of4-fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidinehydrochloride (4.0 g, 9.01 mmol), 2-chloro-5-ethyl-pyrimidine (1.55 g,1.2 eq.) and DIPEA (4.7 g, 4 eq.) in 2-propanol (30 mL) in a sealedpressure vessel was stirred at 160° C. (oil bath temperature) overnight.After cooling, the solvent was removed in vacuo. The residue waspartitioned between water and EtOAc. The organic phase was washed withbrine and dried over Na₂SO₄. After removal of the solvent, the crudeproduct was purified on silica gel (EtOAc:hexanes=1:1) to afford thedesired product as a white solid. ¹H NMR (CDCl₃): δ 8.19 (2H, s), 7.87(2H, d, J=9.2 Hz), 7.36 (1H, s), 7.10 (2H, d, J=9.2 Hz), 5.23 (2H, s),4.69 (2H, m), 3.44 (2H, m), 3.03 (3H, s), 2.48 (2H, q, J=7.6 Hz),2.15˜2.39 (4H, m), 1.21 (3H, t, J=7.6 Hz).

Example 894-Fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

Step 1: 4-Hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butylester

To a cooled (−78° C.) and stirred solution of n-BuLi (2.6 mL, 1.05 eq.,10.0 M in hexanes) in dry Et₂O (20 mL) was added dropwise a solution of2-bromothiazole (4.0 g, 24.4 mmol) in THF (10 mL) over a 10 minuteperiod. After the yellow mixture had been stirred at −78° C. for 30minutes, a solution of 1-Boc-4-piperidone (4.9 g, 1 eq.) in THF (20 mL)was added slowly. The mixture was then continued to stir for another 30minutes before the reaction was quenched by addition of water (5 mL).The mixture was warmed to room temperature and extracted with EtOAc. Theorganic phase was separated, washed with brine and dried over Na₂SO₄.After removal of the solvent, the crude product was purified on silicagel (45% EtOAc in hexanes) to afford the desired product as a thick oil.

Step 2: 4-Fluoro-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butylester

To a solution of 4-hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acidtert-butyl ester (4.36 g, 15.3 mmol) in CH₂Cl₂ (50 mL) at 0° C. wasadded DAST (2.4 mL, 1.2 eq.). The reaction mixture was stirred for 30minutes before it was quenched by addition of saturated NaHCO₃ solution(20 mL). The organic phase was separated and dried over Na₂SO₄. Afterremoval of the solvent, the crude product was purified on silica gel(EtOAc:hexanes=1:4) to afford the desired product as a pale yellow oil.

Step 3:4-Fluoro-4-(5-hydroxymethyl-thiazol-2-yl)-piperidine-1-carboxylic acidtert-butyl ester

To a cooled (−78° C.) and stirred solution of4-fluoro-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester(3.65 g, 12.7 mmol) in THF (20 mL) was added n-BuLi (1.33 mL, 1.05 eq.,10.0 M in hexanes). The mixture was stirred at this temperature for 30minutes. Then a suspension of paraformaldehyde (383 mg, 1 eq.) in THF(10 mL) was added in. The resulting mixture was continued to stir at−78° C. for another 30 minutes and gradually warmed to room temperatureovernight. The reaction was quenched by addition of water (10 mL). Themixture was extracted with EtOAc. The organic phase was washed withbrine and dried over Na₂SO₄. After removal of the solvent, the crudeproduct was purified on silica gel (60% EtOAc in hexanes) to afford thedesired product as a pale yellow solid.

Step 4: 4-(5-Chloromethyl-thiazol-2-yl)-4-fluoro-piperidine-1-carboxylicacid tert-butyl ester

To a mixture of4-fluoro-4-(5-hydroxymethyl-thiazol-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (1.34 g, 4.24 mmol) and pyridine (426 mg, 1.3 eq.) inCH₂Cl₂ (30 mL) at 0° C. was added MsCl (631 mg, 1.3 eq.). The mixturewas warmed to room temperature and stirred overnight. The reactionmixture was washed with saturated NaHCO₃ solution and dried over Na₂SO₄.Removal of the solvent afforded the desired product, which was useddirectly in the following reaction without further purification.

Step 5:4-Fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of4-(5-Chloromethyl-thiazol-2-yl)-4-fluoro-piperidine-1-carboxylic acidtert-butyl ester (1.42 g, 4.24 mmol), 4-methanesulfonyl-phenol (731 mg,1.0 eq.) and K₂CO₃ (878 mg, 1.5 eq.) in acetone (30 mL) was heated toreflux overnight. After cooling, the solid was filtered off through apad of celite. The filtrate was concentrated in vacuo. The crude productwas purified on silica gel (EtOAc:hexanes=1:1) to afford the desiredproduct as a white solid. ¹H NMR (CDCl₃): δ 7.86 (2H, d, J=9.2 Hz), 7.35(1H, s), 7.10 (2H, d, J=9.2 Hz), 5.22 (2H, s), 4.08 (2H, br), 3.19 (2H,br), 3.02 (3H, s), 2.05˜2.32 (4H, m), 1.46 (9H, s).

Example 905-Ethyl-2-{4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

Step 1:4-Fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidinehydrochloride

To a solution of4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (Example 89, 1.30 g, 2.76 mmol) in methanol (5 mL)was added 4 N HCl in dioxane (10 mL). The resulting solution was stirredovernight. The mixture was then evaporated to dryness in vacuo to affordthe desired product as a white solid.

Step 2:5-Ethyl-2-{4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

A solution of4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidinehydrochloride (1.2 g, 2.76 mmol), 2-chloro-5-ethyl-pyrimidine (425 mg,1.1 eq.) and DIPEA (1.4 g, 4 eq.) in 2-propanol (20 mL) in a sealedpressure vessel was stirred at 160° C. (oil bath temperature) overnight.After cooling, the solvent was removed in vacuo. The residue waspartitioned between water and EtOAc. The organic phase was washed withbrine and dried over Na₂SO₄. After removal of the solvent, the crudeproduct was purified on silica gel (EtOAc:hexanes=1:1) to afford thedesired product as a white solid. ¹H NMR (CDCl₃): δ 8.19 (2H, s), 7.90(2H, d, J=8.8 Hz), 7.73 (1H, d), 7.10 (2H, d, J=8.8 Hz), 5.31 (2H, s),4.67 (2H, m), 3.44 (2H, m), 3.04 (3H, s), 2.48 (2H, q, J=7.6 Hz),2.13˜2.38 (4H, m), 1.20 (3H, t, J=7.6 Hz).

Example 914-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperazine-1-carboxylicacid tert-butyl ester

Step 1: 4-(4-Ethoxycarbonyl-thiazol-2-yl)-piperazine-1-carboxylic acidtert-butyl ester

A mixture of 2-bromo-thiazole-4-carboxylic acid ethyl ester (1.4 g, 5.93mmol), piperazine-1-carboxylic acid tert-butyl ester (1.16 g, 1.05 eq.)and DIPEA (1.15 g, 1.5 eq.) in 1,4-dioxane (20 mL) was heated to refluxovernight. After cooling, the solvent was removed in vacuo. The crudeproduct was purified on silica gel (EtOAc:hexanes=1:4) to afford thedesired product as a pale yellow solid.

Step 2: 4-(4-Hydroxymethyl-thiazol-2-yl)-piperazine-1-carboxylic acidtert-butyl ester

A solution of 4-(4-ethoxycarbonyl-thiazol-2-yl)-piperazine-1-carboxylicacid tert-butyl ester (1.15 g, 3.37 mmol) in THF (15 mL) at 0° C. wastreated with LiAlH₄ (128 mg, 1 eq.). The mixture was stirred for 1 hour,then the reaction was quenched with 2 N NaOH solution. The solid wasfiltered off through a pad of celite and washed with EtOAc (100 mL). Thefiltrate was washed with water and dried over Na₂SO₄. Removal of thesolvent afforded the desired product as an oil.

Step 3: 4-(4-Chloromethyl-thiazol-2-yl)-piperazine-1-carboxylic acidtert-butyl ester

To a solution of4-(4-hydroxymethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butylester (848 mg, 2.83 mmol) and DIPEA (550 mg, 1.5 eq.) in CH₂Cl₂ (10 mL)was added MsCl (285 □L, 1.3 eq.) dropwise. The resulting mixture wasstirred overnight. The reaction solution was then concentrated in vacuo.The crude product was purified on silica gel (EtOAc:hexanes=1:4) toafford the desired product as an oil.

Step 4:4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperazine-1-carboxylicacid tert-butyl ester

A mixture of 4-(4-Chloromethyl-thiazol-2-yl)-piperazine-1-carboxylicacid tert-butyl ester (700 m g, 2.20 mmol), 4-methanesulfonyl-phenol(417 mg, 1.1 eq.) and K₂CO₃ (609 mg, 2 eq.) in acetone (30 mL) washeated to reflux overnight. After cooling, the solid was filtered offthrough a pad of celite. The filtrate was concentrated in vacuo. Thecrude product was purified on silica gel (EtOAc:hexanes=1:1) to affordthe desired product as an off-white solid. ¹H NMR (CDCl₃): δ 7.87 (2H,d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 6.59 (1H, s), 5.05 (2H, s), 3.56(4H, m), 3.48 (4H, m), 3.04 (3H, s), 1.49 (9H, s).

Example 921-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-4-(2-methyl-propane-1-sulfonyl)-piperazine

Step 1: 1-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperazinehydrochloride

To a solution of4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperazine-1-carboxylicacid tert-butyl ester (Example 91, 430 mg, 0.95 mmol) in methanol (5 mL)was added 4 N HCl in dioxane (5 mL). The resulting solution was stirredfor 30 minutes at room temperature. The mixture was then evaporated todryness in vacuo to afford the desired product as a pale yellow solid.

Step 2:1-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-4-(2-methyl-propane-1-sulfonyl)-piperazine

A solution of1-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperazinehydrochloride (100 mg, 0.26 mmol) and DIPEA (134 mL, 3 eq.) in CH₂Cl₂ (5mL) was added isobutanesulfonyl chloride (41 mL, 1.2 eq.). The mixturewas stirred for 1 hour, then the reaction solution was directly purifiedon silica gel (EtOAc:hexanes=1:1) to afford the desired product as apale yellow solid. ¹H NMR (CDCl₃): δ 7.87 (2H, d, J=8.8 Hz), 7.12 (2H,d, J=8.8 Hz), 6.62 (1H, s), 5.05 (2H, s), 3.61 (4H, m), 3.39 (4H, m),3.04 (3H, s), 2.78 (2H, d, J=6.8 Hz), 2.32 (1H, m), 1.12 (6H, d, J=6.8Hz).

Example 934-[4-Methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-(5-Hydroxymethyl-4-methyl-thiazol-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (1.00 g, 3.2 mmol) in THF (6.4 mL) was added,4-tetrazol-1-yl-phenol (0.52 g, 3.2 mmol), polymer boundtriphenylphosphine (3 mmol/g, 1.6 g). To this solution was addedditertierybutylazodicarboxylate (1.1 g, 4.8 mmol), stirred for 4 hoursand filtered through a pad of celite. The filtrate was concentrated andpurified by silica gel chromatography to provide the desired product. ¹HNMR (CDCl₃): δ 9.01 (1H, s), 7.66 (2H, d), 7.15 (2H, d), 5.21 (2H, s),4.19 (2H, m), 3.10 (1H, m), 2.86 (2H, m), 2.45 (3H, s), 2.08 (2H, m),1.72 (2H, m), 1.47 (9H, s).

Example 944-{4-[(6-Fluoro-pyridin-3-ylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylicacid tert-butyl ester

5-amino-2-fluoropyridine (0.476 g, 4.2 mmol) was added to4-(4-Formyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester(0.84 g, 2.8 mmol) in dry DCM (10 mL). Sodium triacetoxyborohydride (0.9g, 4.2 mmol) was then added. The reaction was stirred for 3 hours atroom temperature under N₂. The organic layer was washed with 2M NaOHsolution, water, brine, dried (MgSO₄), and the solvent was removed invacuo. The material was purified by silica gel chromatography(DCM/methanol: 10:1 v/v) to give the desired product. ¹H NMR (CDCl₃): δ7.59-7.60 (1H, m), 7.06-7.10 (1H, m), 7.02 (1H, s), 6.76 (1H, dd, J=8.8,3,6 Hz), 4.4 (2H, d), 4.20-4.31 (3H, m), 3.09-3.17 (1H, m), 2.8-2.95(2H, m), 2.07-2.10 (2H, m), 1.77-1.47, (2H, m), 1.47 (9H, s).

Example 951-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidineStep 1:4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carbonitrile

To a mixture of4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine (1.00 g,2.92 mmol) and potassium carbonate (1.5 g, 10.9 mmol) in chloroform (25mL) was added cyanogen bromide (0.371 g, 3.5 mmol). The slurry wasrefluxed for 48 hours then stirred at room temperature for an additional48 hours. The reaction was filtered through a pad of celite,concentrated and chromatographed on silica gel (1:1 Hexanes/EtOAc) toafford the desired compound.

Step 2:1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

To a solution of4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carbonitrile(0.450, 1.22 mmol) and N-hydroxy-isobutyramidine (0.150 g, 1.47 mmol) indry THF (10 mL) was added a 1 M solution of zinc chloride in THF (1.47mL, 1.47 mmol) over 15 min. The suspension was left to settle for 15minutes and the white precipitate was collected by filtration anddissolved in 4N HCl in ethanol and water (1:1). The solution wasrefluxed for 1 hour, cooled and the solid precipitate was filtered off.The filtrate was neutralized by the addition of excess sodium carbonate.The excess was filtered off and the filtrate was diluted with EtOAc. Thesolution was washed with water, separated, dried (Na₂SO₄), filtered andconcentrated. The residual oil was chromatographed on silica gel (1:1Hex/EtOAc) to afford the desired compound. ¹H NMR (CDCl₃): δ 8.92 (1H,s), 7.62 (2H, d), 7.28 (1H, s), 7.19 (2H, d), 5.24 (2H, s), 4.26 (2H,m), 3.20 (3H, m), 2.89 (1H, m), 2.26 (2H, m), 1.92 (2H, m), 1.30 (6H,d).

The following three examples were synthesized in similar manner asExample 95 using the required hydroxy amidine and4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carbonitrile.

Example 961-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

¹H NMR (CDCl₃): δ 8.85 (1H, s), 7.57 (2H, d), 7.28 (1H, s), 7.19 (2H,d), 5.17 (2H, s), 4.22 (2H, m), 3.22 (3H, m), 2.55 (2H, q), 2.17 (2H,m), 1.89 (2H, m), 1.35 (3H, t).

Example 971-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

¹H NMR (CDCl₃): δ 8.90 (1H, s), 7.61 (2H, d), 7.27 (1H, s), 7.17 (2H,d), 5.23 (2H, s), 4.22 (2H, m), 3.22 (3H, m), 2.25 (2H, m), 1.88 (3H,m), 0.96 (4H, m).

Example 984-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-1-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-piperidine

¹H NMR (CDCl₃): δ 8.92 (1H, s), 7.60 (2H, d), 7.23 (1H, s), 7.16 (2H,d), 5.21 (2H, s), 4.25 (2H, m), 4.15 (2H, m), 3.22 (1H, m), 2.90 (2H,m), 2.18 (2H, m).

Example 994-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid amide Step 1:4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carbonitrile

To a mixture of4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine (1.00 g,2.92 mmol) and potassium carbonate (1.5 g, 10.9 mmol) in chloroform (25mL) was added cyanogen bromide (0.371 g, 3.5 mmol). The slurry wasrefluxed for 48 hours then stirred at room temperature for an additional48 hours. The reaction was filtered through a pad of celite,concentrated and chromatographed on silica gel (1:1 Hexanes/EtOAc) toafford the desired compound.

Step 2:4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid amide

4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carbonitrile(1.07 g, 2.92 mmol) was dissolved in 4 N HCl in ethanol/water (1:1). Thesolution was refluxed for 1 hour, cooled and the solid precipitate wasfiltered off. The filtrate was neutralized by the addition of excesssodium carbonate. The excess sodium carbonate was filtered off and thefiltrate was diluted with EtOAc. The solution was washed with water,separated, dried (Na₂SO₄), filtered and concentrated. The residual oilwas chromatographed on silica gel (1:1 Hexanes/EtOAc) to afford thedesired compound. ¹H NMR (CDCl₃): δ 8.92 (1H, s), 7.60 (2H, d), 7.23(1H, s), 7.167 (2H, d), 5.21 (2H, s), 4.25 (2H, m), 4.15 (2H, m), 3.22(1H, m), 2.90 (2H, m), 2.18 (2H, m).

Example 1004-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxamidine

A mixture of4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine (300 mg,0.876 mmol), pyrazole-1-carboxamidine hydrochloride (0.128 g, 0.876mmol.) and triethylamine (0.122 mL, 0.876 mmol) in DMF (2 mL) wasstirred at rt for 3 hours. The precipitate was collected by filtrationand washed with ether to afford the expected product. ¹H NMR (DMSO-d₆):δ 10.02 (1H, s), 7.93 (1H, s), 7.82 (2H, m), 7.70 (1H, s), 7.60 (2H,br), 7.28 (2H, m), 5.20 (2H, s), 3.95 (2H, m), 3.38 (1H, m), 3.15 (2H,m), 2.09 (2H, m), 1.66 (2H, m).

Example 1013-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-azetidine-1-carboxylicacid tert-butyl ester Step 1:3-(4-chloromethyl-thiazol-2-yl)-azetidine-1-carboxylic acid tert-butylester

To a solution of 3-Thiocarbamoyl-azetidine-1-carboxylic acid tert-butylester (0.800 g, 3.7 mmol) in acetone (15 mL) was added1,3-dichloroacetone (0.611 g, 4.81 mmol), MgSO₄ (0.67 g, 5.6 mmol) andMgCO₃ (3.12 g, 3.7 mmol). The mixture was heated under reflux overnight,cooled and filtered through celite. The solvent was removed in vacuo andthe residue was redissolved with EtOAc (20 mL). The resulting solutionwas washed successively with 5% NaHSO₃, saturated NaHCO₃, and brine.After drying (Na₂SO₄), the solvent was removed to afford the desiredproduct which was used without further purification.

Step 2:3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-azetidine-1-carboxylicacid tert-butyl ester

A mixture of 3-(4-chloromethyl-thiazol-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (From Step 1) (386 mg, 1.34 mmol),4-tetrazol-1-yl-phenol (217 mg, 1.34 mmol), Cs₂CO₃ (655 mg, 2.01 mmol)and KI (22 mg, 0.13 mmol) in acetonitrile (5 mL) was heated under refluxfor 4 hours. After cooling, the solid was filtered through a pad ofcelite. The filtrate was concentrated in vacuo. The residue was purifiedon silica gel (EtOAc-hexanes, 1:1) to afford the desired product. ¹H NMR(CDCl₃): δ 8.92 (1H, s), 7.61 (2H, d), 7.32 (1H, s), 7.19 (2H, d), 5.25(2H, s), 4.39 (2H, m), 4.18 (2H, m), 4.14 (1H, m), 1.46 (9H, s).

Example 1023-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

Step 1: 3-(4-Chloromethyl-thiazol-2-yl)-pyrrolidine-1-carboxylic acidtert-butyl ester

To a solution of 3-thiocarbamoyl-pyrrolidine-1-carboxylic acidtert-butyl ester (1.06 g, 4.60 mmol) in acetone (25 mL) was added1,3-dichloroacetone (0.76 g, 5.98 mmol), MgSO₄ (0.83 g, 6.1 mmol) andMgCO₃ (3.87 g, 4.6 mmol). The mixture was heated under reflux overnight,cooled and filtered through celite. The solvent was removed in vacuo andthe residue was redissolved with EtOAc (20 mL). The resulting solutionwas washed successively with 5% NaHSO₃, saturated NaHCO₃, and brine.After drying (Na₂SO₄), the solvent was removed to afford the desiredproduct which was used without further purification.

Step 2:3-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

A mixture of 3-(4-Chloromethyl-thiazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester (From Step 1) (775 mg, 2.56 mmol),4-tetrazol-1-yl-phenol (415 mg, 2.56 mmol), CsCO₃ (1.25 mg, 3.84 mmol)and KI (44 mg, 0.26 mmol) in acetonitrile (20 mL) was heated underreflux overnight. After cooling, the solid was filtered through a pad ofcelite. The filtrate was concentrated in vacuo. The residue was purifiedon silica gel (EtOAc-hexanes, 1:1) to afford the desired product. ¹H NMR(CDCl₃): δ 8.92 (1H, s), 7.63 (2H, d), 7.27 (1H, s), 7.17 (2H, d), 5.24(2H, s), 3.87 (1H, m), 3.79 (1H, m), 3.65 (2H, m), 3.45 (1H, m), 2.40(1H, m), 2.23 (1H, m), 1.47 (9H, s).

Example 1035-Ethyl-2-{3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-pyrrolidin-1-yl}-pyrimidineStep 1:1-[4-(2-Pyrrolidin-3-yl-thiazol-4-ylmethoxy)-phenyl]-1H-tetrazole

A solution of3-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (from Example 102) (411 mg, 0.959 mmol) indichloromethane (10 mL) and methanol (2 mL) were treated with 1 mL of 4NHCl in dioxane. The resulting solution was stirred at room temperaturefor 30 minutes. The solvents were removed in vacuo to afford the desiredproduct as an HCl salt.

Step 2:5-Ethyl-2-{3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-pyrrolidin-1-yl}-pyrimidine

A mixture of1-[4-(2-Pyrrolidin-3-yl-thiazol-4-ylmethoxy)-phenyl]-1H-tetrazolehydrochloride (From Step 1) (350 mg, 0.959 mmol), 2-chloropyrimidine(0.23 mL, 2.0 eq.) and K₂CO₃ (398 mg, 2.88 mmol) in DMF (5 mL) washeated at 90° C. for 4 hours. Water was added and the solution wasextracted with ethyl acetate, separated, dried over sodium sulfate,filtered and concentrated. The residue was purified on silica gel (50:50EtOAc/hexanes) to afford the desired product. ¹H NMR (CDCl₃): δ 8.91(1H, s), 8.21 (2H, s), 7.62 (2H, d), 7.27 (1H, s), 7.17 (2H, d), 5.24(2H, s), 4.12 (1H, m), 3.98 (1H, m), 3.87 (2H, m), 3.69 (1H, m), 2.56(1H, m), 2.47 (2H, m), 2.37 (1H, m), 1.21 (3H, t).

Example 1043-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

Step 1: 3-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acidtert-butyl ester

To a solution of 3-Thiocarbamoyl-piperidine-1-carboxylic acid tert-butylester (2.2 g, 9.02 mmol) in acetone (45 mL) was added1,3-dichloroacetone (1.49 g, 11.7 mmol), MgSO₄ (1.63 g, 13.5 mmol) andMgCO₃ (0.76 g, 9.02 mmol). The mixture was heated under refluxovernight, cooled and filtered through celite. The solvent was removedin vacuo and the residue was redissolved with EtOAc (20 mL). Theresulting solution was washed successively with 5% NaHSO₃, saturatedNaHCO₃, and brine. After drying (Na₂SO₄), the solvent was removed toafford the desired product which was used without further purification.

Step 2:3-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of 3-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (From Step 1) (300 mg, 0.946 mmol),4-tetrazol-1-yl-phenol (155 mg, 0.946 mmol), CsCO₃ (467 mg, 1.42 mmol)and KI (16 mg, 0.095 mmol) in acetonitrile (10 mL) was heated underreflux for 4 hours. After cooling, the solid was filtered through a padof celite. The filtrate was concentrated in vacuo. The residue waspurified on silica gel (EtOAc-hexanes, 1:1) to afford the desiredproduct. ¹H NMR (CDCl₃): δ 8.91 (1H, s), 7.63 (2H, d), 7.26 (1H, s),7.17 (2H, d), 5.24 (2H, s), 4.30 (1H, br), 4.02 (1H, m), 3.20 (1H, m),3.10 (1H, br), 2.88 (1H, t), 2.21 (1H, m), 1.77 (2H, m), 1.61 (1H, m),1.47 (9H, s).

Example 1055-Ethyl-2-{3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidineStep 1: 3-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

A solution of3-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (500 mg, 1.13 mmol) in dichloromethane (10 mL) andmethanol (2 mL) were treated with 2 mL of 4N HCl in dioxane. Theresulting solution was stirred at room temperature for 30 minutes. Thesolvents were removed in vacuo to afford the desired product as an HClsalt.

Step 2:5-Ethyl-2-{3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

A mixture of3-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidinehydrochloride (150 mg, 0.407 mmol), 2-chloropyrimidine (0.074 mL, 2.0eq.) and NaHCO₃ (171 mg, 2.03 mmol) in DMF (5 mL) was heated at 90° C.for 4 hours. Water was added and the solution was extracted with ethylacetate, separated, dried over sodium sulfate, filtered andconcentrated. The residue was purified on silica gel (50:50EtOAc/hexanes) to afford the desired product. ¹H NMR (CDCl₃): δ 8.91(1H, s), 8.19 (2H, s), 7.63 (2H, m), 7.26 (1H, s), 7.17 (2H, m), 5.25(2H, s), 4.97 (1H, m), 4.62 (1H, m), 3.25 (2H, m), 3.07 (1H, m), 2.46(2H, q), 2.28 (1H, m), 1.88 (2H, m), 1.68 (1H, m), 1.20 (3H, t).

Example 1064-[4-(4-Methanesulfonyl-benzyloxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

Hydroxybenzyl-4-methylsulfone (1.7 eq.) was dissolved in anhydrous DMF(10 mL), cooled to 0° C. and NaH (2 eq.) was added in one portion. Thereaction was allowed to stir at 0° C. for 30 minutes and at roomtemperature for an additional 30 minutes.4-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butylester (Intermediate 1) (0.632 mmol) was added and the reaction wasstirred overnight. The reaction was quenched with water and extractedwith EtOAc, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(EtOAc/hexanes 1:1) to afford the desired product. ¹H NMR (CDCl₃): δ7.92 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 7.14 (1H, s), 4.71 (2H,s), 4.66 (2H, s), 4.19 (2H, m), 3.13 (1H, m), 3.05 (3H, s), 2.86 (2H,m), 2.09 (2H, m), 1.72 (2H, m), 1.45 (9H, s).

Example 1072-{4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidin-5-ylamine

5-Nitro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine(Example 192) (1.07 mmol), ammonium chloride (3 eq.) and iron powder (3eq.) were suspended in EtOH:THF:H2O (40:20:10) and heated at 100° C. for5 hours. The hot reaction mixture was filtered through a pad of celiteand the filtrate was concentrated. The resulting oil was dissolved inDMF and water and extracted with ethylacetate. The organic layer waswashed with water, brine and dried over sodium sulfate. The resultingfiltrate was concentrated under reduced pressure. Purification usingsilica gel chromatography (DCM/MeOH 98:2) provided the expected product.¹H NMR (DMSO-d₆): δ 9.96 (1H, s), 7.97 (2H, m), 7.90 (2H, m), 7.63 (1H,s), 5.19 (2H, s), 4.44 (2H, m), 3.73 (1H, m), 2.97 (2H, m), 2.20 (2H,m), 1.95 (2H, m).

Example 108N-(2-{4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-acetamide

2-{4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidin-5-ylamine(Example 107) (0.32 mmol) was dissolved in DCM and triethylamine (2 eq.)was added. The reaction was cooled to 0° C., acetylchloride (1 eq.) wasadded dropwise and the reaction was stirred at room temperatureovernight. Water was added and the mixture was extracted with ethylacetate, dried over sodium sulfate, filtered and concentrated underreduced pressure. Silica gel chromatography of the resulting oil(DCM/MeOH) provided the expected product. ¹H NMR (CDCl₃): δ 8.84 (1H,s), 8.36 (2H, s), 7.55 (2H, m), 7.19 (1H, s), 7.11 (2H, m), 6.94 (1H,s), 5.16 (2H, s), 4.77 (2H, m), 3.25 (1H, m), 3.01 (2H, m), 2.16 (2H,m), 2.15 (3H, s), 1.75 (2H, m).

Example 1094-[4-(4-Tetrazol-1-yl-phenylcarbamoyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

4-(4-Carboxy-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester(1.28 mmol) was dissolved in anhydrous DMF (20 mL). To the solution wasadded triethylamine (4 eq.) andO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (1.5 eq.). The reaction was allowed to stir at room temperaturefor 5 minutes before 4-tetrazol-1-yl-phenylamine (1.2 eq.) was added.The reaction was stirred overnight, quenched with water, extracted withethylacetate, washed with brine, dried over sodium sulfate and filtered.The organic filtrate was concentrated in vacuo and the residual oil waspurified by column chromatography (EtOAC/Hex) furnishing the expectedproduct. ¹H NMR (CDCl₃): δ 9.37 (1H, s), 9.02 (1H, s), 8.14 (1H, s),7.96 (2H, d), 7.72 (2H, d), 4.23 (2H, m), 3.20 (1H, m), 2.91 (2H, m),2.14 (2H, m), 1.79 (2H, m), 1.45 (9H, s).

Example 1104-[4-(4-Trifluoromethanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of[4-(4-Trifluoromethanesulfanyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (Example 134) (1.12 mmol) in DCM (20 mL) at roomtemperature was added 3-chloro-benzenecarboperoxoic acid (2 eq.). Thereaction was allowed to stir for 1.5 hours and an additional portion of3-chloro-benzenecarboperoxoic acid (1 eq.) was added to the reactionmixture. The reaction was stirred at room temperature for an additional4 hours. The organic solution was washed with sodium bicarbonate, theorganic layer was isolated, dried over sodium sulfate and filtered. Thefiltrate was concentrated and the crude product was purified by columnchromatography to afford both the expected sulfone and sulfoxideproducts. Sulfone: ¹H NMR (DMSO-d₆): δ 8.05 (2H, d, J=8.6 Hz), 7.70 (1H,s), 7.44 (2H, d, J=8.6 Hz), 5.32 (2H, s), 3.98 (2H, m), 3.19 (1H, m),2.86 (2H, m), 2.02 (2H, m), 1.56 (2H, m), 1.38 (9H, s).

Example 1114-[4-(4-Trifluoromethanesulfinyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

This compound was isolated from the reaction mixture of the previousexample. ¹H NMR (DMSO-d₆): δ 8.02 (2H, d, J=8.6 Hz), 7.75 (1H, s), 7.32(2H, d, J=8.6 Hz), 5.31 (2H, s), 3.96 (2H, m), 3.20 (1H, m), 2.85 (2H,m), 2.02 (2H, m), 1.50 (2H, m), 1.38 (9H, s).

Example 112-145 were synthesized from4-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butylester (Intermediate 1),2-[4-(4-Chloromethyl-thiazol-2-yl)-piperidin-1-yl]-5-ethyl-pyrimidine(Intermediate 2) or4-(4-Chloromethyl-oxazol-2-yl)-piperidine-1-carboxylic acid tert-butylester (Intermediate 14) with the corresponding phenol, thiophenol, amineor aniline in a similar manner to that described in Example 1. Oneskilled in the art of organic synthesis will appreciate that conditionssuch as solvent (such as DMF, CH₃CN); temperature, base (such as NEt₃,K₂CO₃, NaHCO₃, Na₂CO₃, Cs₂CO₃) and concentration can be selected throughroutine experimentation to optimize yields. Additionally, alternativecoupling methods can be used that are well known in the art of organicsynthesis.

Example 1124-[4-(2,6-Difluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 8.98 (1H, s), 7.34 (2H, m), 7.30 (1H, s), 5.36 (2H,s), 4.19 (2H, m), 3.15 (1H, m), 2.87 (2H, m), 2.07 (2H, m), 1.70 (2H,m), 1.47 (9H, s).

Example 1134-[4-(4-Pyrrol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.24 (3H, m), 7.01 (4H, m), 6.31 (2H, m), 5.17 (2H,s), 4.21 (2H, m), 3.14 (1H, m), 2.87 (2H, m), 2.01 (2H, m), 1.74 (2H,m), 1.47 (9H, s).

Example 1144-{4-[(4-Tetrazol-1-yl-phenylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 8.85 (1H, s), 7.40 (2H, m), 7.01 (1H, s), 6.72 (2H,m), 4.76 (1H, s), 4.44 (2H, s), 4.15 (2H, m), 3.08 (1H, m), 2.83 (2H,m), 2.04 (2H, m), 1.66 (2H, m), 1.43 (9H, s).

Example 1152-{4-[4-(3-Chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-5-ethyl-pyrimidine

¹H NMR (CDCl₃): δ 8.93 (1H, s), 8.18 (2H, s), 7.48 (1H, m), 7.25 (1H,s), 7.08 (2H, m), 5.22 (2H, s), 4.82 (2H, m), 3.29 (1H, m), 3.04 (2H,m), 2.46 (2H, q), 2.21 (2H, m), 1.80 (2H, m), 1.18 (3H, t).

Example 116N-(4-{2-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yl]-thiazol-4-ylmethoxy}-phenyl)-formamide

¹H NMR (CDCl₃): δ 8.55-8.30 (1H, m), 8.18 (2H, s), 7.50-6.90 (6H, m),5.14 (2H, s), 4.83 (2H, m), 3.29 (1H, m), 3.03 (2H, m), 2.46 (2H, q),2.20 (2H, m), 1.80 (2H, m), 1.19 (3H, t).

Example 117N-(4-{2-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yl]-thiazol-4-ylmethoxy}-phenyl)-methanesulfonamide

¹H NMR (CDCl₃): δ 8.20 (s, 2H), 7.21 (m, 3H), 6.95 (m, 2H), 5.13 (s,2H), 4.81 (m, 2H), 3.29 (m, 1H), 3.06 (m, 2H), 2.94 (s, 3H), 2.47 (q,2H), 2.20 (m, 2H), 1.81 (m, 2H), 1.19 (t, 3H).

Example 1184-[4-(2-Methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 8.89 (1H, s), 7.48 (1H, s), 7.43 (1H, m), 7.25 (1H,m), 7.05 (1H, m), 5.27 (2H, s), 4.27 (2H, m), 3.18 (1H, m), 2.89 (2H,m), 2.37 (3H, s), 2.21 (2H, m), 1.74 (2H, m), 1.47 (9H, s).

Example 1195-Ethyl-2-{4-[4-(4-tetrazol-1-yl-2-trifluoromethyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.97 (1H, s), 8.18 (2H, s), 7.92 (1H, m), 7.84 (1H,m), 7.33 (1H, m), 7.26 (1H, s), 5.38 (2H, s), 4.81 (2H, m), 3.27 (1H,m), 3.05 (2H, m), 2.46 (2H, q), 2.19 (2H, m), 1.79 (2H, m), 1.19 (3H,t).

Example 1202-{4-[4-(2-Chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-5-ethyl-pyrimidine

¹H NMR (acetone-d₆), δ 9.68 (1H, s), 8.24 (2H, s), 8.01 (1H, s), 7.86(1H, m), 7.60 (1H, m), 7.59 (1H, s), 5.40 (2H, s), 4.82 (2H, m), 3.36(1H, m), 3.08 (2H, m), 2.48 (2H, q), 2.17 (2H, m), 1.75 (2H, m), 1.18(3H, t).

Example 1214-[4-(4-Tetrazol-1-yl-phenoxymethyl)-oxazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 8.94 (1H, s), 7.65 (1H, s), 7.60 (2H, m), 7.13 (2H,m), 5.01 (2H, s), 4.08 (2H, m), 2.94 (3H, m), 2.03 (2H, m), 1.75 (2H,m), 1.43 (9H, s).

Example 1224-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-oxazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 8.88 (1H, s), 7.62 (1H, s), 7.45 (1H, m), 7.36 (1H,m), 7.23 (1H, m), 5.05 (2H, s), 4.04 (2H, m), 2.85 (3H, m), 1.97 (2H,m), 1.71 (2H, m), 1.40 (9H, s).

Example 1235-Ethyl-2-{4-[4-(4-methanesulfonyl-phenoxymethyl)-oxazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.16 (2H, s), 7.84 (2H, m), 7.63 (1H, s), 7.08 (2H,m), 5.02 (2H, s), 4.67 (2H, m), 3.08 (3H, m), 3.01 (3H, s), 2.44 (2H,q), 2.12 (2H, m), 1.84 (2H, m), 1.17 (3H, t).

Example 1244-[4-(2,6-Difluoro-4-propionyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.51 (2H, d), 7.27 (1H, s), 5.37 (2H, s), 4.18 (2H,m), 3.14 (1H, m), 2.92 (2H, q, J=7.4 Hz), 2.88 (2H, m), 2.07 (2H, m),1.71 (2H, m), 1.47 (9H, s), 1.21 (3H, t, J=7.4 Hz).

Example 1254-[4-(4-Acetyl-2-fluoro-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.70˜7.72 (2H, m), 7.28 (1H, s), 7.09˜7.13 (1H, m),5.30 (2H, s), 4.20 (2H, m), 3.17 (1H, m), 2.88 (2H, m), 2.55 (3H, s),2.10 (2H, m), 1.72 (2H, m), 1.47 (9H, s).

Example 1264-[4-(4-Cyano-2-fluoro-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.37˜7.42 (2H, m), 7.27 (1H, s), 7.13˜7.17 (1H, m),5.28 (2H, s), 4.20 (2H, m), 3.15 (1H, m), 2.89 (2H, m), 2.09 (2H, m),1.72 (2H, m), 1.47 (9H, s).

Example 1274-[4-(6-Tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 9.41 (1H, s), 8.27 (1H, d), 8.01 (1H, d), 7.58 (1H,dd), 7.28 (1H, s), 5.27 (2H, s), 4.20 (2H, m), 3.14-3.20 (1H, m), 2.87(2H, m), 2.09-2.12 (2H, m), 1.68-1.78 (2H, m), 1.46 (9H, s)

Example 1284-[4-(4-[1,2,3]Triazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.92 (1H, s), 7.84 (1H, s), 7.65 (2H, d), 7.25 (1H,s), 7.11 (2H, d), 5.22 (2H, s), 4.21 (2H, br), 3.18 (1H, m), 2.88 (2H,br), 2.12 (2H, m), 1.75 (2H, m), 1.47 (9H, s).

Example 1294-[4-(4-Ethoxycarbonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 8.01 (2H, d), 7.23 (1H, s), 7.01 (2H, d), 5.22 (2H,s), 4.36 (2H, q), 4.22 (2H, br), 3.17 (1H, m), 2.87 (2H, br), 2.12 (2H,m), 1.75 (2H, m), 1.47 (9H, s), 1.39 (2H, t).

Example 1304-[4-(4-tert-Butoxycarbonylamino-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.28 (2H, d), 7.19 (1H, s), 6.92 (2H, d), 6.40 (1H,s), 5.12 (2H, s), 4.22 (2H, br), 3.17 (1H, m), 2.87 (2H, br), 2.12 (2H,m), 1.75 (2H, m), 1.50 (9H, s), 1.47 (9H, s).

Example 1314-[4-(4-Carboxy-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (DMSO-d₆): δ 7.86 (2H, d), 7.64 (1H, s), 7.10 (2H, d), 5.17 (2H,s), 3.96 (2H, m), 3.18 (1H, m), 2.87 (2H, br), 1.96 (2H, m), 1.49 (2H,m), 1.38 (9H, s).

Example 1324-[4-(2,6-Difluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.42 (2H, d), 7.21 (1H, s), 5.25 (2H, s), 4.12 (2H,br), 3.17 (1H, m), 3.00 (3H, s), 2.87 (2H, br), 1.98 (2H, m), 1.71 (2H,m).

Example 1334-[4-(4-Morpholin-4-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.19 (1H, s), 6.92 (4H, m), 5.12 (2H, s), 4.20 (2H,br), 3.85 (4H, br), 3.16 (1H, m), 3.07 (4H, m), 2.86 (2H, m), 2.10 (2H,m), 1.72 (2H, m), 1.47 (9H, s).

Example 1344-[4-(4-Trifluoromethylsulfanyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (DMSO-d₆): δ 7.64 (1H, s), 7.63 (2H, d, J=8.6 Hz), 7.17 (2H, d,J=8.6 Hz), 5.17 (2H, s), 3.99 (2H, m), 3.18 (1H, m), 2.83 (2H, m), 2.01(2H, m), 1.52 (2H, m), 1.38 (9H, s).

Example 1354-[4-(4-Benzyloxy-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (DMSO-d₆): δ 7.55 (1H, s), 7.41 (5H, m), 6.92 (4H, m), 5.12 (4H,s), 3.98 (2H, m), 3.20 (1H, m), 2.84 (2H, m), 2.01 (2H, m), 1.52 (2H,m), 1.38 (9H, s).

Example 1364-[4-(2-Acetylamino-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 8.81 (1H, s), 7.97 (1H, s), 7.53 (1H, d), 7.25 (1H,s), 7.09 (1H, d), 5.24 (2H, s), 4.16 (2H, m), 3.10 (3H, m), 2.83 (2H,m), 2.16 (3H, s), 2.04 (2H, d), 1.66 (2H, m), 1.40 (9H, s), 1.19 (3H,t).

Example 137 4-(4-Phenoxymethyl-thiazol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.28 (2H, m), 7.19 (1H, s), 6.93 (3H, m), 5.14 (2H,s), 4.19 (2H, s), 3.15 (1H, m), 2.85 (2H, m), 2.07 (2H, d), 1.67 (2H,m), 1.45 (9H, s).

Example 1384-{4-[(4-Methanesulfonyl-phenylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.67 (2H, d, J=8.8 Hz), 6.99 (1H, s), 6.67 (2H, d,J=8.8 Hz), 5.07 (1H, m), 4.45 (2H, d), 4.18 (2H, s), 3.13 (1H, m), 2.97(3H, s), 2.85 (2H, m), 2.04 (2H, d), 1.68 (2H, m), 1.44 (9H, s).

Example 1394-{4-[(2-Fluoro-4-methanesulfonyl-phenylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylicacid isopropyl ester

¹H NMR (CDCl₃): δ 7.55 (2H, m), 7.05 (1H, s), 6.76 (1H, m), 5.12 (1H,m), 4.52 (2H, d), 4.19 (2H, m), 3.13 (1H, m), 3.05 (3H, s), 2.86 (2H,m), 2.10 (2H, m), 1.76 (2H, m), 1.46 (9H, s).

Example 1404-[4-(4-Bromo-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acidtert-butyl ester

¹H NMR (CDCl₃): δ 7.36 (2H, m), 7.17 (1H, s), 6.82 (2H, m), 5.10 (2H,s), 4.18 (2H, s), 3.13 (1H, m), 2.85 (2H, m), 2.09 (2H, d), 1.75 (2H,m), 1.43 (9H, s).

Example 141{2-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yl]-thiazol-4-ylmethyl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine

¹H NMR (CDCl₃): δ 8.16 (2H, s), 7.52 (2H, m), 7.01 (1H, s), 6.74 (1H,m), 5.15 (1H, m), 4.83 (2H, m), 4.51 (2H, d), 3.26 (1H, m), 3.02 (5H,m), 2.46 (2H, m), 2.19 (2H, m), 1.78 (2H, m), 1.19 (3H, t).

Example 1424-{4-[(4-Methanesulfonyl-benzylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.85 (2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.8 Hz), 6.95(1H, s), 4.14 (2H, s), 3.87 (2H, s), 3.83 (2H, s), 3.11 (1H, m), 3.04(3H, s), 2.86 (2H, m), 2.07 (3H, m), 1.67 (2H, m), 1.42 (9H, s).

Example 1434-(4-{[1-(4-Methanesulfonyl-phenyl)-ethylamino]-methyl}-thiazol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 7.87 (2H, d, J=8.8 Hz), 7.56 (2H, d, J=8.8 Hz), 6.87(1H, s), 4.22 (2H, m), 3.90 (1H, s), 3.66 (2H, m), 3.09 (1H, m), 3.04(3H, s), 2.82 (3H, m), 2.02 (2H, m), 1.71 (2H, m), 1.40 (9H, s), 1.29(3H, d).

Example 1443-Methyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 8.93 (1H, s), 7.61 (2H, m), 7.25 (1H, m), 7.12 (2H,m), 5.22 (2H, m), 4.2 (1H, m), 3.95 (1H, m), 3.33 (1H, m), 3.13 (1H, m),2.8 (1H, m), 2.34 (1H, m), 2.04 (1H, m), 1.89 (1H, m), 1.45 (9H, s),0.85 (3H, m).

Example 1454-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl₃): δ 9.07 (1H, s), 7.51 (1H, m), 7.41 (1H, m), 7.23 (2H,m), 5.25 (2H, s), 4.16 (1H, m), 3.88 (1H, m), 3.34 (1H, m), 3.09 (1H,m), 2.8 (1H, m), 2.26 (1H, m), 1.96 (1H, m), 1.83 (1H, m), 1.39 (9H, s),0.76 (3H, m).

Examples 146-157 were synthesized from one of Intermediates 3-13 orIntermediates 15-25 with the corresponding sulfonyl chloride, alkylchloride, alkyl bromide, chloroformate, acid chloride, carbamyl chlorideor isocyanate in a manner similar to that described in Example 22. Oneskilled in the art of organic synthesis will appreciate that conditionssuch as solvent (e.g., DMF, CH₃CN); temperature, base (e.g., NEt₃,K₂CO₃, NaHCO₃, Na₂CO₃, Cs₂CO₃) and concentration can be selected throughroutine experimentation to optimize yields. Additionally, alternativecoupling methods can be used that are well known in the art of organicsynthesis.

Example 1464-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid allyl ester

¹H NMR (CDCl₃), δ 9.00 (1H, s), 7.54 (1H, m), 7.45 (1H, m), 7.29 (2H,m), 5.95 (1H, m), 5.30 (3H, m), 5.22 (1H, m), 4.61 (2H, m), 4.28 (2H,m), 3.20 (1H, m), 2.98 (2H, m), 2.14 (2H, m), 1.78 (2H, m).

Example 1474-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid cyclohexyl ester

¹H NMR (CDCl₃): δ 8.91 (1H, s), 7.60 (2H, m), 7.25 (1H, s), 7.16 (2H,m), 5.22 (2H, s), 4.68 (1H, m), 4.36 (2H, m), 3.19 (1H, m), 2.91 (2H,m), 2.12 (2H, m), 1.88 (6H, m), 1.40 (6H, m).

Example 1484-[4-(2-Fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid isopropyl ester

¹H NMR (CDCl₃): δ 7.64˜7.70 (2H, m), 7.20˜7.26 (2H, m), 5.29 (2H, s),4.89˜4.95 (1H, m), 4.24 (2H, m), 3.13˜3.19 (1H, m), 3.03 (3H, s),2.86˜2.93 (2H, m), 2.11 (2H, m), 1.69˜1.78 (2H, m), 1.23 (6H, d, J=6.4Hz).

Example 1491-Isopropyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 7.79 (2H, d, J=8.8 Hz), 7.63 (1H, s),7.28 (2H, d, J=8.8 Hz), 5.19 (2H, s), 2.91 (1H, m), 2.82 (2H, m), 2.68(1H, m), 2.20 (2H, m), 2.01 (2H, m), 1.63 (2H, m), 0.94 (6H, d, J=6.4Hz).

Example 1501-Propyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

¹H NMR (DMSO-d₆): δ 9.97 (1H, s), 7.80 (2H, d, J=8.8 Hz), 7.64 (1H, s),7.28 (2H, d, J=8.8 Hz), 5.20 (2H, s), 2.94 (1H, m), 2.88 (2H, m), 2.22(2H, t, J=7.2 Hz), 1.99 (4H, m), 1.64 (2H, m), 1.41 (2H, m), 0.83 (3H,t, J=7.2 Hz).

Example 1513,3-Dimethyl-1-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-butan-2-one

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 7.80 (2H, d, J=8.8 Hz), 7.64 (1H, s),7.28 (2H, d, J=8.8 Hz), 5.20 (2H, s), 3.41 (2H, s), 2.95 (1H, m), 2.82(2H, m), 2.18 (2H, m), 1.98 (2H, m), 1.69 (2H, m), 1.07 (9H, s).

Example 1521-Butyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

¹H NMR (DMSO-d₆): δ 9.97 (1H, s), 7.80 (2H, d, J=8.8 Hz), 7.64 (1H, s),7.28 (2H, d, J=8.8 Hz), 5.20 (2H, s), 2.94 (1H, m), 2.88 (2H, m), 2.26(2H, t, J=6.8 Hz), 1.98 (4H, m), 1.66 (2H, m), 1.39 (2H, m), 1.26 (2H,m), 0.86 (3H, t, J=7.2 Hz).

Example 1532-{4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone

¹H NMR (DMSO-d₆): δ 9.97 (1H, s), 8.14 (2H, d, J=6.4 Hz), 8.02 (2H, d,J=6.4 Hz), 7.80 (2H, d, J=8.8 Hz), 7.64 (1H, s), 7.28 (2H, d, J=8.8 Hz),5.20 (2H, s), 3.84 (2H, s), 2.98 (1H, m), 2.93 (2H, m), 2.38 (2H, m),2.00 (2H, m), 1.68 (2H, m).

Example 1541-Methanesulfonyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 7.81 (2H, d, J=8.8 Hz), 7.69 (1H, s),7.29 (2H, d, J=8.8 Hz), 5.21 (2H, s), 3.60-3.63 (2H, m), 3.32 (3H, s),3.12-3.18 (1H, m), 2.83-2.90 (2H, m), 2.14-2.17 (2H, m), 1.71 (2H, m).

Example 1554-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid heptyl ester

¹H NMR (CDCl₃): δ 8.91 (1H, s), 7.60 (2H, d), 7.25 (1H, s), 7.19 (2H,d), 5.24 (2H, s), 4.26 (2H, br), 4.09 (2H, t), 3.20 (1H, m), 2.94 (2H,m), 2.16 (2H, m), 1.77 (2H, m), 1.60 (2H, m), 1.32 (8H, m), 0.90 (3H,t).

Example 1564-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-1-(toluene-4-sulfonyl)-piperidine

¹H NMR (CDCl₃): δ 8.91 (1H, s), 7.67 (2H, d, J=8.8 Hz), 7.59 (2H, d,J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.25 (1H, s), 7.15 (2H, m), 5.19 (2H,s), 3.91 (2H, d), 2.95 (1H, m), 2.44 (3H, s), 2.37 (2H, m), 2.17 (2H,d), 1.94 (2H, m).

Example 1572-tert-Butoxy-1-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-ethanone

¹H NMR (DMSO-d₆): δ 9.99 (1H, s), 7.81 (2H, m), 7.26 (2H, m), 5.20 (2H,s), 4.36 (1H, m), 3.97 (3H, m), 3.28 (1H, m), 3.12 (1H, m), 2.71 (1H,m), 2.04 (2H, m), 1.67 (1H, m), 1.46 (1H, m), 1.13 (9H, s).

Examples 158-205 were synthesized from one of Intermediates 3-13 orIntermediates 15-25 with the corresponding 2-chloropyrimidine,2-iodopyrimidine, 2-chloropyridine, 2-fluoropyridine,2-methanesulfonyl-pyrimidine, 2-chloropyrazine, 2-chloropyridazine orother suitable heterocycles in a manner similar to that described inExample 47. One skilled in the art of organic synthesis will appreciatethat conditions such as solvent (such as DMF, CH₃CN); temperature, base(such as NEt₃, K₂CO₃, NaHCO₃, Na₂CO₃, Cs₂CO₃) and concentration can beselected through routine experimentation to optimize yields.Additionally, alternative coupling methods can be used that are wellknown in the art of organic synthesis.

Example 1585-Ethyl-2-{4-[4-(3-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 9.04 (1H, s), 8.19 (2H, s), 7.78 (1H, m), 7.28 (1H,s), 6.70 (2H, m), 5.23 (2H, s), 4.83 (2H, m), 3.31 (1H, m), 3.05 (2H,m), 2.47 (2H, q), 2.21 (2H, m), 1.81 (2H, m), 1.20 (3H, t).

Example 1592-{4-[4-(2,6-Difluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-5-ethyl-pyrimidine

¹H NMR (CDCl₃): δ 8.95 (1H, s), 8.17 (2H, s), 7.34 (2H, m), 7.28 (1H,s), 5.35 (2H, s), 4.76 (2H, m), 3.27 (1H, m), 3.04 (2H, m), 2.46 (2H,q), 2.16 (2H, m), 1.76 (2H, m), 1.19 (3H, t).

Example 1605-Ethyl-2-{4-[4-(4-pyrrol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.18 (2H, s), 7.29 (2H, m), 7.20 (1H, s), 6.99 (4H,m), 6.31 (2H, m), 5.17 (2H, s), 4.84 (2H, m), 3.28 (1H, m), 3.03 (2H,m), 2.46 (2H, q), 2.21 (2H, m), 1.81 (2H, m), 1.19 (3H, t).

Example 161{2-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yl]-thiazol-4-ylmethyl}-(4-tetrazol-1-yl-phenyl)-amine

¹H NMR (CDCl₃): δ 8.83 (1H, s), 8.16 (2H, s), 7.41 (2H, m), 7.02 (1H,s), 6.74 (2H, m), 4.82 (1H, s), 4.79 2H, s), 4.45 (2H, m), 3.25 (1H, m),3.01 (2H, m), 2.44 (2H, q), 2.17 (2H, m), 1.77 (2H, m), 1.11 (3H, t).

Example 1622-{4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-5-isopropyl-pyrimidine

¹H NMR (CDCl₃): δ 8.92 (1H, s), 8.21 (2H, s), 7.51 (1H, m), 7.40 (1H,m), 7.29 (1H, s), 7.26 (1H, m), 5.30 (2H, s), 4.82 (2H, m), 3.28 (1H,m), 3.04 (2H, m), 2.77 (1H, m), 2.20 (2H, m), 1.80 (2H, m), 1.23 (6H,d).

Example 163

¹H NMR (CDCl₃): δ 8.97 (1H, s), 7.80 (1H, s), 7.50 (1H, m), 7.40 (1H,m), 7.27 (1H, s), 7.24 (1H, m), 5.27 (2H, s), 4.42 (4H, m), 3.24 (1H,m), 3.04 (9H, m), 2.16 (2H, m), 1.88 (2H, m).

Example 1645-Ethyl-2-{4-[4-(2-methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.88 (1H, s), 8.19 (2H, s), 7.48 (1H, s), 7.44 (1H,m), 7.24 (1H, m), 7.05 (1H, m), 5.26 (2H, s), 4.83 (2H, m), 3.27 (1H,m), 3.05 (2H, m), 2.47 (2H, q), 2.37 (3H, s), 2.22 (2H, m), 1.81 (2H,m), 1.19 (3H, t).

Example 1655-Chloro-2-{4-[4-(2-chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (acetone-d₆), δ 9.68 (1H, s), 8.33 (2H, s), 8.01 (1H, s), 7.86(1H, m), 7.60 (1H, m), 7.59 (1H, s), 5.40 (2H, s), 4.78 (2H, m), 3.40(1H, m), 3.16 (2H, m), 2.20 (2H, m), 1.77 (2H, m).

Example 1662-{4-[4-(2-Chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-5-trifluoromethyl-pyrimidine

¹H NMR (acetone-d₆), δ 9.68 (1H, s), 8.62 (2H, s), 8.01 (1H, s), 7.86(1H, m), 7.61 (1H, s), 7.60 (1H, m), 5.41 (2H, s), 4.92 (2H, m), 3.46(1H, m), 3.27 (2H, m), 2.25 (2H, m), 1.80 (2H, m).

Example 1672-{4-[4-(2-Isopropyl-5-methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-5-trifluoromethyl-pyrimidine

¹H NMR (CDCl₃): δ 8.73 (1H, s), 8.46 (2H, s), 7.22 (1H, s), 7.10 (1H,s), 6.90 (1H, s), 5.24 (2H, s), 4.93 (2H, m), 3.35 (2H, m), 3.17 (2H,m), 2.23 (2H, m), 2.09 (3H, s), 1.82 (2H, m), 1.20 (6H, d).

Example 1685-Chloro-2-{4-[4-(2-isopropyl-5-methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.73 (1H, s), 8.20 (2H, s), 7.21 (1H, s), 7.09 (1H,s), 6.90 (1H, s), 5.24 (2H, s), 4.78 (2H, m), 3.35 (1H, m), 3.28 (1H,m), 3.07 (2H, m), 2.19 (2H, m), 2.09 (3H, s), 1.79 (2H, m), 1.20 (6H,d).

Example 1695-Ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-oxazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.91 (1H, s), 8.18 (2H, s), 7.65 (1H, s), 7.60 (2H,m), 7.15 (2H, m), 5.03 (2H, s), 4.69 (2H, m), 3.10 (3H, m), 2.44 (2H,q), 2.14 (2H, m), 1.86 (2H, m), 1.19 (3H, t).

Example 1705-Ethyl-2-{4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-oxazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.93 (1H, s), 8.17 (2H, s), 7.67 (1H, s), 7.50 (1H,m), 7.41 (1H, m), 7.29 (1H, m), 5.11 (2H, s), 4.67 (2H, m), 3.08 (3H,m), 2.45 (2H, q), 2.12 (2H, m), 1.84 (2H, m), 1.18 (3H, t).

Example 1712-{4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-5-trifluoromethyl-pyrimidine

¹H NMR (CDCl₃): δ 8.91 (1H, s), 8.49 (2H, s), 7.52 (1H, d, J=7.6 Hz),7.41 (1H, d, J=7.6 Hz), 7.32 (1H, s), 7.29 (1H, m), 5.32 (2H, s), 4.95(2H, m), 3.37 (1H, m), 3.15 (2H, m), 2.24 (2H, m), 1.81 (2H, m).

Example 1725-Decyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (DMSO-d₆): δ 9.97 (1H, s), 8.21 (2H, s), 7.80 (2H, d, J=8.8 Hz),7.65 (1H, s), 7.28 (2H, d, J=8.8 Hz), 5.20 (2H, s), 4.66 (2H, m), 3.32(1H, m), 3.01 (2H, m), 2.37 (2H, m), 2.09 (2H, m), 1.60 (2H, m), 1.45(2H, m), 1.21 (14H, m), 0.82 (3H, m).

Example 1736-Methyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine-4-carboxylicacid methyl ester

¹H NMR (DMSO-d₆): δ 9.97 (1H, s), 7.80 (2H, d, J=8.8 Hz), 7.66 (1H, s),7.28 (2H, d, J=8.8 Hz), 7.01 (1H, s), 5.21 (2H, s), 4.76 (2H, m), 3.84(3H, s), 3.33 (1H, m), 3.06 (2H, m), 2.36 (3H, s), 2.14 (2H, m), 1.61(2H, m).

Example 1744-Chloro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.91 (1H, s), 8.15 (1H, d, J=5.2 Hz), 7.60 (2H, d,J=8.8 Hz), 7.25 (1H, s), 7.16 (2H, d, J=8.8 Hz), 6.49 (1H, d, J=5.2 Hz),5.22 (2H, s), 4.85 (2H, m), 3.30 (1H, m), 3.07 (2H, m), 2.21 (2H, m),1.80 (2H, m).

Example 1752-Chloro-4-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.90 (1H, s), 8.05 (1H, d, J=6.4 Hz), 7.61 (2H, d,J=8.8 Hz), 7.28 (1H, s), 7.17 (2H, d, J=8.8 Hz), 6.46 (1H, d, J=6.4 Hz),5.23 (2H, s), 4.45 (2H, m), 3.35 (1H, m), 3.15 (2H, m), 2.27 (2H, m),1.85 (2H, m).

Example 1766-Methyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine-4-carboxylicacid

¹H NMR (DMSO-d₆): δ 13.3 (1H, br), 9.97 (1H, s), 7.80 (2H, d, J=8.8 Hz),7.66 (1H, s), 7.28 (2H, d, J=8.8 Hz), 6.98 (1H, s), 5.21 (2H, s), 4.79(2H, m), 3.34 (1H, m), 3.05 (2H, m), 2.35 (3H, s), 2.13 (2H, m), 1.62(2H, m).

Example 1775-Chloro-4,6-difluoro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.91 (1H, s), 7.61 (2H, d, J=8.8 Hz), 7.27 (1H, s),7.16 (2H, d, J=8.8 Hz), 5.23 (2H, s), 4.69 (2H, m), 3.32 (1H, m), 3.10(2H, m), 2.23 (2H, m), 1.80 (2H, m).

Example 1784-Fluoro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (DMSO-d₆): δ 9.97 (1H, s), 8.41 (1H, m), 7.80 (2H, d, J=8.0 Hz),7.66 (1H, s), 7.28 (2H, d, J=8.0 Hz), 6.34 (1H, m), 5.20 (2H, s), 4.60(2H, m), 3.32 (1H, m), 3.10 (2H, m), 2.11 (2H, m), 1.61 (2H, m).

Example 1792-Fluoro-4-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 8.08 (1H, m), 7.80 (2H, d, J=9.2 Hz),7.67 (1H, s), 7.28 (2H, d, J=9.2 Hz), 6.84 (1H, m), 5.20 (2H, s), 4.40(2H, m), 3.40 (1H, m), 3.14 (2H, m), 2.13 (2H, m), 1.63 (2H, m).

Example 1802-{4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-thiazole-5-carboxylicacid ethyl ester

¹H NMR (DMSO-d₆): δ 9.97 (1H, s), 7.84 (1H, m), 7.80 (2H, d, J=9.0 Hz),7.68 (1H, s), 7.28 (2H, d, J=9.0 Hz), 5.21 (2H, s), 4.19 (2H, t, J=7.20Hz), 4.03 (2H, m), 3.35 (3H, m), 2.15 (2H, m), 1.75 (2H, m), 1.23 (3H,t, J=7.20 Hz).

Example 1814-Imidazol-1-yl-6-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 8.59 (1H, s), 8.43 (1H, s), 8.01 (1H,d, J=1.2 Hz), 7.81 (2H, d, J=8.8 Hz), 7.67 (1H, s), 7.27 (2H, d, J=8.8Hz), 7.14 (1H, s), 7.10 (1H, d, J=1.2 Hz), 5.20 (2H, s), 4.61 (2H, m),3.40 (1H, m), 3.15 (2H, m), 2.15 (2H, m), 1.66 (2H, m).

Example 1825-Ethyl-2-{4-[4-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 9.44 (1H, s), 8.28 (1H, d, J=3.0 Hz), 8.2 (2H, s),8.02, (1H, d, J=8.8 Hz), 7.58 (1H, dd, J=8.8 Hz, 3.0 Hz), 7.27 (1H, s),5.27 (2H, s), 4.82-4.85 (2H, m), 3.22-3.35 (1H, m), 3.0-3.1, (2H, m),2.47 (2H, q, J=7.2 Hz), 2.2-2.23 (2H, m), 1.76-1.86 (2H, m), 1.19 (3H,t, J=7.2 Hz).

Example 1835-Methyl-2-{4-[4-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (DMSO-d₆): δ 10.07 (1H, s), 8.42 (1H, d, J=3.0 Hz), 8.21 (2H, s),7.99 (1H, d, J=9.2 Hz), 7.86 (1H, dd, J=9.2 Hz, 3.0 Hz), 7.70 (1H, s),5.30 (2H, s), 4.62 (2H, m), 3.56-3.60 (1H, m), 2.98-3.04 (2H, m), 2.06(3H, s), 1.72-1.76 (2H, m), 1.59 (2H, m).

Example 1845-Chloro-2-{4-[4-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃) δ 9.44 (1H, s), 8.28 (1H, d, J=3.0 Hz), 8.23 (2H, s),8.02 (1H, d, J=9.0 Hz), 7.58 (1H, dd, J=9.0 Hz, 3.0 Hz), 7.28 (1H, s),5.27 (2H, s), 4.8-4.83 (2H, m), 3.22-3.38 (1H, m), 3.04-3.11 (2H, m),2.20-2.23 (2H, m), 1.80 (2H, m)

Example 1852-{4-[4-(6-Tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl]-piperidin-1-yl}-5-trifluoromethyl-pyrimidine

¹H NMR (DMSO-d₆): δ 10.07 (1H, s), 8.68 (2H, s), 8.42 (1H, d, J=3.0 Hz),7.99 (1H, d, J=9.2 Hz), 7.86 (1H, dd, J=9.2 Hz, 3.0 Hz), 7.72 (1H, s),5.73 (2H, s), 4.74-4.77 (2H, m), 3.37-3.43 (1H, m), 3.15-3.21 (2H, m),2.12-2.16 (2H, m), 1.59-1.68 (2H, m).

Example 1863-Chloro-6-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyridazine

¹H NMR (CDCl₃): δ 8.91 (1H, s), 7.61 (2H, d, J=9.0 Hz), 7.26 (1H, s),7.22 (1H, d, J=9.6 Hz), 7.17 (2H, d, J=9.0 Hz), 6.95 (1H, d, J=9.6 Hz),5.23 (2H, s), 4.43-4.47 (2H, m), 3.31-3.37 (1H, m), 3.12-3.19 (2H, m),2.25-2.28 (2H, m), 1.90 (2H, m).

Example 1872-Tetrazol-1-yl-5-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrazine

¹H NMR (DMSO-d₆): δ 9.97 (2H, s), 8.67 (1H, s), 8.37 (1H, s), 7.80 (2H,d, J=8.8 Hz), 7.67 (1H, s), 7.28 (2H, d, J=8.8 Hz), 5.21 (2H, s),4.50-4.53 (2H, m), 3.38-3.44 (1H, m), 3.17-3.23 (2H, m), 2.15-2.18 (2H,m), 1.69-1.77 (2H, m).

Example 188{2-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yl]-thiazol-4-ylmethyl}-(6-fluoro-pyridin-3-yl)-amine

¹H NMR (CDCl₃): δ 8.19 (2H, s), 7.58-7.62 (1H, m), 7.05-7.10 (1H, m),7.01 (1H, s), 6.75 (1H, dd, J=8.4 Hz, 2.8 Hz), 4.81-4.85 (2H, m), 4.40(2H, d, J=5.2 Hz), 4.29 (1H, br s), 3.23-3.29 (1H, m), 3.00-3.06 (2H,m), 2.47 (2H, q, J=7.6 Hz), 2.18-2.20 (2H, m), 1.79 (2H, m), 1.20 (3H,t, J=7.6 Hz).

Example 1892-{4-[4-(2,6-Difluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-5-ethyl-pyrimidine

¹H NMR (CDCl₃): δ 8.19 (2H, s), 7.51 (2H, d), 7.25 (1H, s), 5.40 (2H,s), 4.82 (2H, m), 3.30 (1H, m), 3.06 (3H, s), 3.03 (2H, m), 2.48 (2H,q), 2.15 (2H, m), 1.74 (2H, m), 1.20 (3H, t).

Example 1905-Butyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.92 (1H, s), 8.17 (2H, s), 7.62 (2H, m), 7.25 (1H,s), 7.17 (2H, m), 5.24 (2H, s), 4.83 (2H, m), 3.30 (1H, m), 3.04 (2H,m), 2.42 (2H, t), 2.23 (2H, m), 1.84 (2H, m), 1.52 (2H, m), 1.34 (2H,m), 0.92 (3H, m).

Example 1914-(4-{2-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yl]-thiazol-4-ylmethoxy}-phenyl)-morpholine

¹H NMR (CDCl₃): δ 8.18 (2H, s), 7.19 (1H, s), 6.92 (4H, m), 5.12 (2H,s), 4.84 (2H, m), 3.86 (4H, br), 3.30 (1H, m), 3.05 (6H, m), 2.46 (2H,q), 2.21 (2H, m), 1.78 (2H, m), 1.19 (3H, t).

Example 1925-Nitro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (DMSO-d₆): δ 9.91 (1H, s), 9.11 (2H, s), 7.83 (2H, d, J=8.8 Hz),7.68 (1H, s), 7.25 (2H, d, J=8.8 Hz), 5.22 (2H, s), 4.81 (2H, m), 3.39(1H, m), 3.31 (2H, m), 2.23 (2H, s), 1.68 (2H, m).

Example 1933′-Chloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

¹H NMR (CDCl₃): δ 8.91 (1H, s), 8.39 (1H, s), 7.76 (1H, s), 7.61 (2H,m), 7.25 (1H, s), 7.18 (2H, m), 5.24 (2H, s), 4.16 (2H, m), 3.26 (1H,m), 3.06 (2H, m), 2.25 (2H, m), 2.01 (2H, m).

Example 1943′-Chloro-4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

¹H NMR (CDCl₃): δ 8.94 (1H, s), 8.38 (1H, s), 7.75 (1H, s), 7.53 (1H,m), 7.40 (1H, m), 7.31 (1H, s), 7.25 (1H, m), 5.31 (2H, s), 4.15 (2H,d), 3.25 (1H, m), 3.09 (2H, m), 2.23 (2H, d), 1.99 (2H, m).

Example 1955-Chloro-2-{4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.96 (1H, s), 8.20 (2H, s), 7.52 (1H, m), 7.40 (1H,m), 7.28 (1H, s), 7.25 (1H, m), 5.28 (2H, s), 4.78 (2H, m), 3.30 (1H,m), 3.07 (2H, m), 2.20 (2H, m), 1.79 (2H, m).

Example 1963′,5′-Dichloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

¹H NMR (DMSO-d₆): δ 9.98 (1H, s), 8.26 (1H, s), 8.03 (1H, s), 7.81 (2H,d), 7.67 (1H, s), 7.29 (2H, d), 5.21 (2H, s), 3.79 (2H, m), 3.24 (1H,m), 2.97 (2H, m), 2.14 (2H, m), 1.84 (2H, m).

Example 1973′-Chloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylicacid ethyl ester

¹H NMR (CDCl₃): δ 8.92 (1H, s), 8.74 (1H, s), 8.11 (1H, s), 7.61 (2H,d), 7.25 (1H, s), 7.17 (2H, d), 5.23 (2H, s), 4.37 (2H, m), 4.22 (2H,m), 3.31 (1H, m), 3.08 (2H, m) 2.26 (2H, m), 1.98 (2H, m), 1.38 (3H, m).

Example 1985′-Chloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-carboxylicacid methyl ester

¹H NMR (CDCl₃): δ 8.91 (1H, s), 8.20 (1H, s), 7.99 (1H, s), 7.61 (2H,d), 7.25 (1H, s), 7.16 (2H, d), 5.21 (2H, s), 3.91 (2H, m), 3.88 (3H,s), 3.28 (1H, m), 3.08 (2H, m), 2.20 (2H, m), 1.93 (2H, m).

Example 1995-Ethyl-2-{3-methyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.90 (1H, s), 8.18 (2H), 7.60 (2H, m), 7.25 (1H, s),7.17 (2H, m), 5.26 (2H), 4.89-4.51 (2H, m), 3.49-3.20 (2H, m), 2.92 (1H,m), 2.65-2.45 (1H, m), 2.45 (2H, m), 2.17-1.81 (2H, m), 1.20 (3H, m),0.82-0.92 (3H).

Example 2005-Ethyl-2-{4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.93 (1H, s), 8.17 (2H), 7.52-7.25 (4H, m), 5.32 (2H),4.84-4.46 (2H, m), 3.47-3.22 (2H, m), 2.91 (1H, m), 2.62-2.43 (1H, m),2.42 (2H, m), 2.07 (2H, m), 1.18 (3H, m), 0.90-0.79 (3H, m).

Example 2015-Chloro-2-{4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.93 (1H, s), 8.19 (2H), 7.52-7.25 (4H, m), 5.29 (2H),4.82-4.51 (2H, m), 3.46-3.21 (2H, m), 2.95 (1H, m), 2.64-2.42 (1H, m),2.02 (2H, m), 0.90-0.78 (3H, m).

Example 2022-{4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl-piperidin-1-yl}-5-trifluoromethyl-pyrimidine

¹H NMR (CDCl₃): δ 8.94 (1H, s), 8.47 (2H), 7.53-7.27 (4H, m), 5.34 (2H),5.02-4.62 (2H, m), 3.52-2.97 (3H, m), 2.73-2.47 (1H, m), 2.17-2.01 (2H,m), 0.94-0.78 (3H, m).

Example 2035-Ethyl-2-{4-[4-(4-methanesulfonyl-benzyloxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.17 (2H, s), 7.92 (2H, d, J=8.8 Hz), 7.58 (2H, d,J=8.8 Hz), 7.13 (1H, s), 4.83 (2H, m), 4.71 (2H, s), 4.66 (2H, s), 3.27(1H, m), 3.03 (3H, s), 2.98 (2H, m), 2.46 (2H, m), 2.19 (2H, m), 1.76(2H, m), 1.19 (3H, m).

Example 2045-Fluoro-2-{4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine

¹H NMR (CDCl₃): δ 8.91 (1H, s), 8.21 (2H, s), 7.52 (1H, m), 7.41 (1H,m), 7.27 (1H, m), 7.25 (1H, s), 5.31 (2H, s), 4.76 (2H, m), 3.28 (1H,m), 3.06 (2H, m), 2.20 (2H, m), 1.81 (2H, m).

Example 205

¹H NMR (CDCl₃): δ 8.91 (1H, s), 8.49 (2H, s), 7.61 (2H, d), 7.27 (1H,s), 7.17 (2H, d), 5.24 (2H, s), 4.96 (2H, m), 3.38 (1H, m), 3.14 (2H,m), 2.26 (2H, m), 1.82 (2H, m).

Example 2064-(4-{[(4-Methanesulfonyl-phenyl)-methyl-amino]-methyl}-thiazol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester

4-{4-[(4-Methanesulfonyl-phenylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylicacid tert-butyl ester (Example 138) (0.10 mmol) was dissolved in DMF (2mL) and NaH (2 eq.) was added in a single portion at room temperature.The reaction was stirred for 30 minutes and methyliodide (10 eq.) wasadded. After stirring for 3 hours, the reaction was quenched with waterand extracted with EtOAc. The organic layer was washed with brine, driedover sodium sulfate, filtered and concentrated in vacuo. Purification ofthe residue by silica gel chromatography (Hexanes/EtOAc 1:1) providedthe expected product. ¹H NMR (CDCl₃): δ 7.73 (2H, m), 6.78 (2H, m), 6.76(1H, s), 4.70 (2H, s), 4.20 (2H, br), 3.19 (3H, s), 3.12 (1H, m), 3.01(3H, s), 2.87 (2H, m), 2.07 (2H, m), 1.80 (2H, m), 1.47 (9H, s).

Example 207{2-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yl]-thiazol-4-ylmethyl}-(2-fluoro-4-methanesulfonyl-phenyl)-methyl-amine

Example 207 was synthesized in a manner analogous to Example 206utilizing{2-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yl]-thiazol-4-ylmethyl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine(Example 141) as the starting material. ¹H NMR (CDCl₃): δ 8.19 (2H, s),7.47-7.57 (2H, m), 6.94 (1H, s), 6.91 (1H, m), 4.80 (2H, m), 4.62 (2H,s), 3.24 (1H, m), 3.09 (3H, s), 3.03 (3H, s), 3.00 (2H, m), 2.47 (2H,m), 2.17 (2H, m), 1.74 (2H, m), 1.19 (3H, t).

Example 2084-[4-(2-Methylsulfanyl-pyrimidin-5-yloxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

Example 208 was prepared from4-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butylester (Intermediate 1) and 2-Methylsulfanyl-pyrimidin-5-ol in a mannersimilar to that described in Example 1. ¹H NMR (CDCl₃): δ 8.35 (2H, s),7.23 (1H, s), 5.19 (2H, s), 4.22 (2H, m), 3.16 (1H, m), 2.87 (2H, m),2.55 (3H, s), 2.10 (2H, m), 1.71 (2H, m), 1.46 (9H, s).

Example 2094-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid allyl ester

Example 209 was prepared from4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine(Intermediate 4) and allyl chloroformate in a manner similar to thatdescribed in Example 22. ¹H NMR (CDCl₃): δ 8.96 (1H, s), 7.63 (2H, m),7.20 (1H, s), 7.18 (2H, m), 5.96 (1H, m), 5.31 (1H, m), 5.22 (3H, m),4.61 (2H, m), 4.29 (2H, m), 3.21 (1H, m), 2.97 (2H, m), 2.15 (2H, m),1.78 (2H, m).

Example 210 2-{4-[4-Methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-5-trifluoromethyl-pyrimidine

Step 1:4-[4-Methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine

A solution of4-[4-Methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (Example 93) (500 mg, 1.10 mmol) indichloromethane (5 mL) was treated with 1.5 mL of 4N HCl in dioxane. Theresulting solution was stirred at room temperature for 5 hours and allthe solvent were removed in vacuo to afford the desired product as anHCl salt.

Step 2:2-{4-[4-Methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-5-trifluoromethyl-pyrimidine

This compound was prepared from4-[4-Methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidinehydrochloride in a similar manner as described in Example 47. ¹H NMR(CDCl₃): δ 8.94 (1H, s), 8.49 (2H, s), 7.64 (2H, m), 7.14 (2H, m), 5.20(2H, s), 4.95 (2H, m), 3.27 (1H, m), 3.13 (2H, m), 2.46 (3H, s), 2.21(2H, m), 1.77 (2H, m).

Biological Example 1 Stimulation of cAMP

The compounds of the present invention were evaluated in an assaydemonstrating agonism of IC-GPCR2. This assay was developed using astable cell line expressing IC-GPCR-2, generated as follows. IC-GPCR2(Seq. ID No. 1) was cloned into Gateway pDEST 40vector (Invitrogen),using the Gateway cloning system (invitrogen) according to themanufacturer's instructions. A stable cell line was generated bytransfecting a 10 cm plate of CHO cells (source) with Bug of thisconstruct using Transit-CHO transfection kit (Minis). CHO cells wereplated the day prior to transfection at a density of 3,000,000cells/plate. Clones were selected using the antibiotic G418 at 500ug/ml. 23 clones were picked and assayed for the expression of thereceptor by measuring changes in intracellular cAMP levels in responseto an IC-GPCR2 agonist.

To measure cAMP activity in response to IC-GPCR2 agonist, the cloneswere plated in 96 well plates at 17500 cells per well. On the day afterplating, cells were incubated with the IC-CPCR2 agonist at 10 uM for 30minutes in Ham's F12 Media (Gibco) with 0.04% DMSO. cAMP was measuredusing the cAMP dynamic kit from C is Bio (Bedford, Mass.) according tothe manufacturer's instructions. Briefly, cells were lysed, and cAMPlevels determined by competitive immunoassay using D2 labeled cAMP, andeuropium cryptate tagged anti cAMP antibody. When in close proximity,the D2 and europium cryptate undergo fluorescence resonance energytransfer (FRET), which is measured as a fluorescence ratio (665 nm/620nm). Unlabelled cAMP in the cell lysate competed with the D2 labeledcAMP for the europium crypate labeled antibody. The resulting decreasein FRET signal corresponded to intracellular cAMP levels. Fluorescencewas read on a BMG Labtech PHERAstar, software version 1.50.

The clone with the greatest response to IC-GPCR2 agonist was selectedfor the screening assay.

Determination of Activity of Compounds

Compounds were dissolved in 100% DMSO to a concentration of 10 uM toprovide stock solutions. To determine activity against IC-GPCR2,compounds were incubated with IC-GPCR2 stably expressing cells(described above), at 6-8 concentrations ranging from 0.00003 to 10micromolar, in 96 well plates, in 50 ul of Hams F12 media for 30minutes. Cells were plated at 17500 cells per well 1 day before runningthe assay. All compounds were also screened against the parental CHOcells. cAMP was measured using the cAMP dynamic kit from C is Bio(Bedford, Mass.), according to the manufacturer's instructions. Briefly,cells were lysed and cAMP levels determined by competitive immunoassayusing D2 labeled cAMP, and europium cryptate tagged anti cAMP antibody.When in close proximity, the D2 and europium cryptate undergofluorescence resonance energy transfer (FRET), which is measured as afluorescence ratio (665 nm/620 nm). Unlabelled cAMP in the cell lysatecompeted with the D2 labeled cAMP for the europium crypate labeledantibody. The resulting decrease in FRET signal corresponded tointracellular cAMP levels.

Activities of compounds disclosed in Table 1 and Table 2 below areexpressed as the % change in FRET signal from DMSO control. “*” noactivity observed when tested at 10 micromolar but no higherconcentrations were tested. NT indicates the compound was not tested atthe indicated concentration.

TABLE 1 Example # Activity at 10 uM 1 69 2 50 3 63 4 NT 5 60 6 68 7 64 856 9 54 10 NT 11 34 12 70 13 94 14 84 15 55 16 56 17 69 18 72 19 76 2027 21 23 22 62 23 37 24 58 25 23 26 58 27 63 28 62 29 51 30 73 31 88 3288 33 77 34 70 35 64 36 95 37 80 38 39 39  9 40 21 41 75 42 67 43 47 4453 45 84 46 30 47 51 48 NT 49 NT 50 NT 51 57 52 67 53 NT 54 58 55 66 56NT 57  7 58 NT 59 70 60 60 61 NT 62 NT 63 NT 64 NT 65 NT 66 57 67 NT 6853 69 74 70 20 71 88 72 78 73 29 74 17 75 NT 76 74 77 NT 78 43 79 NT 80NT 81 59 82 NT 83 27 84 59 85 NT 86 49 87 62 88 49 89 NT 90 64 91 28 9214

TABLE 2 Example # Activity at 10 uM 93 NT 94 48 95 63 96 79 97 52 98 7899 67 100 NT 101 44 102 49 103 79 104 76 105 52 106 71 107 53 108 NT 10938 110 51 111 68 112 57 113 60 114 68 115 67 116 74 117 65 118 64 119 53120 73 121 75 122 76 123 72 124 80 125 78 126 87 127 NT 128 57 129 43130 53 131 24 132 70 133 61 134 68 135 66 136 * 137 35 138 64 139 NT 14062 141 64 142 78 143 63 144 81 145 73 146 NT 147 56 148 74 149 NT 150 32151 54 152 68 153 44 154 66 155 73 156  6 157 57 158 NT 159 78 160 77161 79 162 79 163 NT 164 68 165 71 166 74 167 NT 168 NT 169 85 170 75171 76 172 NT 173 75 174 NT 175 NT 176 43 177 NT 178 39 179 NT 180 59181 NT 182 78 183 78 184 69 185 83 186 80 187 75 188 69 189 76 190 77191 74 192 74 193 35 194 29 195 68 196 19 197 * 198 15 199 78 200 82 20187 202 83 203 76 204 NT 205 75 206 NT 207 NT 208 NT 209 NT 210 NT

Biological Example 2 Insulin Secretion (Islet Perifusion)

To determine the effect of IC-GPCR2 agonists on insulin secretion fromislets, islets from Sprague Dawley rats were isolated. 200-250 g SpragueDawley rats (Charles River laboratories) were maintained on regular chow(Purina 5001). Before the procedure, rats were anesthetized with intraperitoneal injection of pentobarbital at 200 mg/kg. The bile duct wasclamped where it enters the duodenum, then a catheter was placed in thebile duct between the liver and the pancreas. The pancreas was infusedthrough the catheter with a solution of 0.75 mg/ml collagenase P (Roche)in HBSS buffer (Biowhitaker) supplemented with 0.1% glucose and 0.02%BSA. The pancreas was then excised from the rat and placed in 5 ml ofthe collagenase P solution in a 37° C. waterbath for 8 minutes. After 8minutes the digested pancreas was shaken vigorously by hand for 30seconds. The resulting digest was washed four times in the HBSS buffer,then applied to a discontinuous ficoll gradient. To make the gradient,the digest was resuspended in 7.5 ml of ficoll DL400 solution (Sigma)density 1.108, in a 15 ml tube. Three 2 ml layers of ficoll solution ofdecreasing density (1.096, 1.069, 1.037) were then added to the tube tocreate a density gradient. The gradient was centrifuged at 1500 rpm for15 minutes after which islets were picked from the top two layers.Islets were washed four times in HBSS buffer, then cultured in RPMI 1640media (Gibco) supplemented with 1% fetal bovine serum. The followingday, 25 size-matched islets were placed in a perifusion chamber andexposed to Krebs Ringer Buffer (KRB; 119 mM NaCl, 4.7 mM KCl, 25 mMNaHCO₃, 2.5 mM CaCl₂, 1.2 mM MgSO₄, 1.2 mM KH2PO₄) at a rate of 1ml/minute, using a Cellex Acu-sys S perifusion culture system. Theislets were exposed to KRB containing glucose at 2 mM for 30 minutes,followed with buffer containing 16 mM glucose for 30 minutes, thenreturned to 2 mM glucose for a further 30 minutes, in the presence of 1uM of the IC-GPCR2 agonist or vehicle (DMSO). Perifusate was collectedat 1 minute intervals using a fraction collector, and assayed forinsulin using an ELISA kit (Mercodia Ultrasensitive Rat Insulin ELISAKit, ALPCO). Insulin secretion rate in response to glucose was plottedagainst time, and the AUC of the curve determined in order to quantifythe insulin secretory response to 16 mM glucose during the 30 minuteperifusion. Statistical significance of differences in AUC betweentreated and untreated islets were determined by paired Student's t-test.

The table below shows the fold stimulation of insulin secretion inducedby each of the tested IC-GPCR2 agonists at 16 mM glucose. The testedcompounds were selected as examples from the exemplified compounds.These results demonstrate that the IC-GPCR2 agonists stimulate insulinsecretion in response to glucose.

Fold stimulation of insulin Significance Compound secretion at 16 mMglucose (p value) Agonist 1 1.66 0.01 Agonist 2 1.78 0.04

Biological Example 3 Oral Glucose Tolerance

8-10 week old male C57/6J mice (Harlan) were maintained on regular chowdiet (Purina 5001). The day of the experiment mice were fasted for 6hours, then randomized into groups (n=8) to receive the tested IC-GPCR2agonist at doses ranging from 3-30 mg/kg or the vehicle (1% CMC, 2%TWEEN 80). Compounds were delivered orally via gavage at 10 ml/kg. Bloodglucose levels were measured by glucometer (Ascensia Elite XL, Bayer) attime 0, before administration of compound. Blood glucose was measuredagain after 30 minutes, and then the mice were dosed orally with 2 g/kgglucose at 10 ml/kg. Blood glucose measurements were taken 15, 30, 60,90 and 120 minutes after glucose administration, by glucometer (AscensiaElite XL, Bayer).

Glucose levels were plotted against time and the incremental area underthe curve (AUC) of the glucose excursion was determined from T0 to T120using GraphPad Prism 5.0. Outliers were determined at each time point ofthe OGTT and for the AUC values using Tukey's box plot outlier test.Animals with any outlying points were excluded from the analysis, andstatistical significance of differences in AUC between compoundtreatment and vehicle was determined by non-parametric Kruskal-Wallistest with Dunn's post test. Differences with a p-value≦0.05 wereconsidered significant.

Tables 3 and 4 below show the mean percentage inhibition of the glucoseexcursion. At 30 mg/kg and 3 mg/kg. The values in Tables 3 and 4 thatare marked with an asterisk (*) are significant. These resultsdemonstrate that the IC-GPCR2 agonists can lower blood glucose inresponse to an oral glucose challenge.

TABLE 3 % reduction in AUC at 30 mg/kg Agonist 2 47.6* Agonist 3 NoneAgonist 4 33.0* Agonist 5 39.3 Agonist 6 None Agonist 8 32.6 Agonist 913.9 Agonist 10 57.8* Agonist 11 49.5* Agonist 12 23.7 Agonist 13 22.7Agonist 14 44.7* Agonist 15 18.5 Agonist 16 26.9

TABLE 4 % reduction in AUC at 3 mg/kg Agonist 10 51.5* Agonist 17 29.3Agonist 18 23.7 Agonist 19 2.5 Agonist 20 29.4

Biological Example 4 Tissue Specific Expression

RNA was extracted from isolated rat and mouse islets, and used toprepare double stranded cDNA using standard techniques (see Sambrook etal., Molecular Cloning, A Laboratory Manual (3rd ed. 2001); CurrentProtocols in Molecular Biology (Ausubel et al., eds., 1994)). The cDNAwas cloned into the pZL1 vector (Invitrogen) and the 3′ ends ofindividual clones were sequenced in multiple rounds of sequencingreactions. Sequence data representing approximately 12,000 independentclones were used to construct oligonucleotide probes synthesized on aGENECHIP® (Affymetrix Inc., Santa Clara, Calif.), producing mouse andrat islet chips. RNA from five rat islet preparations (each preparationfrom a different mouse), and preparations from a panel of rat tissues,were hybridized to the rat chips. Expression data was analyzed with theAffymetrix MAS 4.0 algorithm to give relative gene expression values asaverage difference scores, and presence/absence calls. RNA from twopreparations from a mouse beta cell line BHC-9, four mouse isletpreparations (each preparation from a different mouse), and preparationsfrom a panel of mouse tissues, were hybridized to the mouse chips.Expression data was analyzed with the Affymetrix MAS 5.0 algorithm togive relative gene expression values as signal, and presence/absencecalls.

FIGS. 1 (rat) and 2 (mouse) show the tissue specific expression of thereceptor for the novel agonists of the present invention, showing tissuespecificity to pancreatic islet cells (including the beta cellstherein).

Sequence ID No. 1 atggaatcatctttctcatttggagtgatccttgctgtcctggcctccctcatcattgctactaacacactagtggctgtggctgtgctgctgttgatccacaagaatgatggtgtcagtctctgcttcaccttgaatctggctgtggctgacaccttgattggtgtggccatctctggcctactcacagaccagctctccagcccttctcggcccacacagaagaccctgtgcagcctgcggatggcatttgtcacttcctccgcagctgcctctgtcctcacggtcatgctgatcacctttgacaggtaccttgccatcaagcagcccttccgctacttgaagatcatgagtgggttcgtggccggggcctgcattgccgggctgtggttagtgtcttacctcattggcttcctcccactcggaatccccatgttccagcagactgcctacaaagggcagtgcagcttctttgctgtatttcaccctcacttcgtgctgaccctctcctgcgttggcttcttcccagccatgctcctctttgtcttcttctactgcgacatgctcaagattgcctccatgcacagccagcagattcgaaagatggaacatgcaggagccatggctggaggttatcgatccccacggactcccagcgacttcaaagctctccgtactgtgtctgttctcattgggagctttgctctatcctggacccccttccttatcactggcattgtgcaggtggcctgccaggagtgtcacctctacctagtgctggaacggtacctgtggctgctcggcgtgggcaactccctgctcaacccactcatctatgcctattggcagaaggaggtgcgactgcagctctaccacatggccctaggagtgaagaaggtgctcacctcattcctcctctttctcttggccaggaattgtggcccagagaggcccagggaaagttcctgtcacatcgtcactatctcc agctcagagtttgatggctaaSequence ID No. 2 MESSFSFGVILAVLASLIIATNTLVAVAVLLLIHKNDGVSLCFTLNLAVADTLIGVAISGLLTDQLSSPSRPTQKTLCSLRMAFVTSSAAASVLTVMLITFDRYLAIKQPFRYLKIMSGFVAGACIAGLWLVSYLIGFLPLGIPMFQQTAYKGQCSFFAVFHPHFVLTLSCVGFFPAMLLFVFFYCDMLKIASMHSQQIRKMEHAGAMAGGYRSPRTPSDFKALRTVSVLIGSFALSWTPFLITGIVQVACQECHLYLVLERYLWLLGVGNSLLNPLIYAYWQKEVRLQLYHMALGVKKVLTSFLLFLLARNCGPERPRESSCHIVTIS SSEFDG

Biological Example 5 Improvement of Glucose Levels, Insulin Levels, andWeight in High-Fat Fed Female ZDF Rats

The ZDF rat is a leptin receptor deficient model of obesity, hyperphagiaand insulin resistance. Animals develop diabetes due to pancreatic isletfailure in the face of insulin resistance. The males develop diabetesspontaneously between 9 and 11 weeks of age, whereas the females remainnon-diabetic unless placed on a high fat diet. This diet makes theanimals more insulin resistant, and the increased demand for insulin isbelieved to precipitate islet failure. The female ZDF rats usuallybecome diabetic within 2 weeks of being placed on a high fat diet(Corsetti et al; 2000).

Five week old female ZDF rats were obtained and were acclimatized for 9days. The rats were then sorted into 8 study groups based on bodyweight, insulin levels and glucose levels. One group was maintained onregular chow, and the other 7 were placed on a high-fat diet. Drug orvehicle treatment was initiated concurrently with the diet. Statisticalsignificance of observed differences was assessed by two way ANOVA withBonferroni post test. Analysis was performed with GraphPad Prism 5.0.

Agonist 2 was dosed orally by gavage in 1% carboxymethylcellulose, 2%Tween 80 (vehicle). Agonist 2 was administered at 10, 30, and 100 mg/kg.Blood samples were collected from the tail vein under non-fastingconditions on days 0, 7, 14, 21 and 35. Blood samples were collectedafter 16 h overnight fast on day 28. Glucose was measured using aglucometer (Ascensia Elite XL, Bayer); insulin was measured using theMercodia Ultrasensitive Rat Insulin ELISA kit (ALPCO). Insulin, glucoseand levels were compared to those of vehicle treated animals todetermine efficacy, and statistical significance of differencesdetermined by one way ANOVA.

Fed Plasma Glucose Levels

FIG. 3 shows the fed plasma glucose levels of the animals during thecourse of the study. High fat fed female ZDF rats showed a progressiveincrease in fed plasma glucose levels during the 35 days of the study.Animals on the chow diet showed only a slight increase in fed plasmaglucose levels over the course of the study. Animals treated withAgonist 2 showed an increase in plasma glucose during the study, butwhen treated with 30 and 100 mg/kg of agonist 2, the treated animals hadstatistically significantly lower plasma glucose than controls at alltime points tested. Animals treated with 10 mg/kg agonist 2 showed lowerplasma glucose levels than vehicle treated high fat fed control animalsbut did not reach a statistical significance of p≦0.05.

Fed Plasma Insulin Levels

FIG. 4 shows the fed plasma insulin levels during the course of thestudy. After 7 days of high-fat feeding, the vehicle treated groupshowed elevated fasting insulin levels compared to the chow fed group.Animals treated with 30 and 100 mg/kg agonist 2 had significantly lowerinsulin levels than the vehicle group after 7 days. After 14 days on ahigh fat diet, the vehicle treated animals still had increased insulinlevels compared to chow fed controls, but the levels were lower than at7 days. Animals treated with agonist 2 at 10, 30 and 100 mg/kg were notsignificantly different from vehicle treatment at 14 days. By day 21 ofhigh-fat feeding, insulin levels in vehicle treated animals had droppedback to levels similar to those seen in chow fed controls, whereasinsulin levels in animals treated with 30 mg/kg and 100 mg/kg agonistwere significantly greater. By day 35 of high fat feeding, insulinlevels in the vehicle group had fallen to levels lower than observed inthe chow fed group, whereas the insulin levels in the groups treatedwith 30 mg/kg and 100 mg/kg agonist 2 were significantly greater than inuntreated animals. Animals treated with 10 mg/kg agonist 2 did not haveinsulin levels significantly different from vehicle treated animals atany time point measured in the study.

Effect of 28 Days of Treatment with Agonist 2 on Fasting Plasma Glucoseand Insulin Levels in High Fat Fed Female ZDF Rats.

After 28 days of high-fat feeding, fasted plasma glucose and insulinlevels were assessed. The data is provided in FIG. 5. Vehicle treatedanimals on the high fat diet had significantly elevated fasting plasmaglucose compared to chow fed controls. Animals treated with 30 and 100mg/kg agonist 2 had fasting plasma glucose levels that weresignificantly lower than vehicle, and similar to chow fed controls.Vehicle treated animals on the high fat diet had similar fasting insulinlevels to chow fed controls. Insulin levels in animals treated withagonist 2 at 30 and 100 mg/kg were significantly elevated compared tothe vehicle group. This reflects the effect of the high fat diet toincrease insulin resistance in these animals. In the absence of drugtreatment the islets are unable to continue to compensate for theinsulin resistance, and insulin levels fall. Treatment with 30 and 100mg/kg agonist 2 allows the islets to continue making the insulinrequired to maintain glucose control in the face of insulin resistance.

The changes in insulin levels seen in the vehicle group on the high-fatdiet reflect the etiology of diabetes development in this model. Theanimals become more insulin resistant due to the high fat diet, and theislets are initially able to compensate for the increased insulinresistance by increasing the output of insulin. This is reflected inhigher plasma insulin levels at day 7 and day 14 of the study. After day14, insulin levels begin to decline as a result of the islet failureinherent to the female ZDF rats. This decline in insulin levelscoincides with an increase in plasma glucose as shown in FIG. 3.Treatment with 30 and 100 mg/kg agonist 2 attenuates the initialincrease in insulin secretion and prevents the subsequent decline.

Biological Example 6 Improvement in Triglyceride Levels in Female ZDFRats

Female ZDF rats (Charles River laboratories) were obtained at 6 weeks ofage and acclimatized for 1 week before being placed on a high fat diet(RD 13004, Research Diets). Rats were divided into control (n=10) andtreatment groups (n=10). Compounds (agonist 2 and agonist 10) wereadministered to the rats by daily gavage in 1% CMC, 2% TWEEN 80. Agonist2 was administered at 30 and 100 mg/kg, agonist 10 at 30 mg/kg. Fedtriglyceride levels were measured at day 28 and fed glucose levels weremeasured at day 32. Glucose was also measured after overnight fast onday 35. Glucose was measured using a glucometer (Ascensia Elite XL,Bayer); insulin was measured using the Mercodia Ultrasensitive RatInsulin ELISA kit (ALPCO). Triglycerides were measured using a SerumTriglyceride Determination Kit (Sigma TR0100). Insulin, glucose andtriglyceride levels were compared to those of vehicle treated animals todetermine efficacy, and statistical significance of differencesdetermined by one way ANOVA.

Table 5 below shows the percentage change in fed triglyceride levels atday 28, in fed glucose levels at day 32 and in fasted glucose levels atday 35 in drug treated vs. vehicle treated animals.

A significant reduction in fed triglyceride level was observed after 28days of treatment with 100 mg/kg agonist 2 and with 30 mg/kg agonist 10compared to vehicle treated animals. A significant reduction of fedplasma glucose was observed after 32 days of treatment with 100 mg/kgagonist 2 and with 30 mg/kg agonist 10 compared to vehicle treatedanimals. A significant reduction in fasted plasma glucose was observedafter 35 days of treatment with 100 mg/kg agonist 2 and with 30 mg/kgagonist 10 compared to vehicle treated animals.

TABLE 5 % Decrease from vehicle group Fed Fasted Treatment plasmaglucose plasma glucose Fed plasma TG Agonist 2 30 mg/kg 22  30  19 Agonist 2 100 mg/kg 56* 52* 34* Agonist 10 30 mg/kg 40* 52* 44* *p ≦0.01, by one way ANOVA.

Biological Example 7 Incretin Measurement

The effect of IC-GPCR2 agonists on the secretion of Glucagon-likepeptide-1 (GLP-1) and GIP in C57/6J mice are determined as follows.

8-10 week old male C57/6J mice (Harlan) are maintained on a regular chowdiet (Purina 5001). On the day of the experiment mice are fasted for 6hours then randomized into groups (n=8). All groups are treated with theDPPIV inhibitor sitagliptin at 100 mg/kg to prevent degredation ofactive GLP-1. IC-GPCR-2 agonist compounds are dosed at concentrationsranging from 0.3-300 mg/kg in 1% CMC, 2% TWEEN 80 at −30 minutes.Sitagliptin is administered in the same dosing solution. Oral glucose at2 g/kg is adminsted at 0 minutes. At 10 minutes after glucoseadministration, animals are anesthetized with pentobarbital (40 mg/ml in10% ethanol) and blood collected by heart puncture in microtainer tubes(BD) with potassium EDTA. For GLP-1 assay, the collection tubes alsocontain a DPP-IV inhibitor provided in the GLP-1 assay kit.

Insulin is measured using the Mercodia mouse Insulin ELISA Kit (ALPCO)according to the manufacturer's instructions. Bioactive GLP-1 ismeasured using Glucagon-like peptide-1 (active) ELISA assay kit (Linco)according to the manufacturer's instructions. GIP is measured usingrat/mouse GIP total ELISA assay kit (Linco), according to themanufacturer's instructions.

All patents, patent applications, publications and presentationsreferred to herein are incorporated by reference in their entirety. Anyconflict between any reference cited herein and the teaching of thisspecification is to be resolved in favor of the latter. Similarly, anyconflict between an art-recognized definition of a word or phrase and adefinition of the word or phrase as provided in this specification is tobe resolved in favor of the latter.

1-61. (canceled)
 62. A compound selected from the group consisting of:

or a salt thereof.
 63. A compound of formula:

or a salt thereof.